Prevention and treatment of viral infections

ABSTRACT

The present disclosure targets the Zika virus and other disease-causing microbes including viruses, bacteria, fungi, and parasites. It does this using agents and methods with little toxicity compared to existing therapies.

This application is a Continuation-in-part of U.S. Ser. No. 16/201,205filed Nov. 27, 2018, which is a bypass continuation-in-part ofPCT/US2017/035150 filed May 31, 2017, which claims benefit of U.S.Provisional Patent Application No. 62/344,591, filed Jun. 2, 2016, whichare incorporated herein by reference in their entirety.

BACKGROUND

The emergence of the Zika virus represents a global health threat(Sikka, V. et al. “The emergence of Zika Virus as a Global HealthSecurity Threat: A Review and Consensus Statement of the INDUSEM JointWorking Groups (JWG). Journal of Global Infectious Diseases. 8 (2016):3-15). The present disclosure represents a method for prevention andtreatment of the Zika virus. It provides physical, chemical, andmetabolic barriers to infection by this pathogenic agent.

The Zika virus is a member of the family Flaviviridae and is an RNAcontaining virus. It is usually transmitted by an Aedes mosquito whichinjects it into the skin with a stinger, causing infection of threetypes of skin cells (epidermal keratinocytes, dermal fibroblasts, dermalmacrophages)(Hamel, R., et al., “Biology of Zika Virus Infection inHuman Skin Cells” J. Virol. 89 (2015):8880-8896.) and then proceeds to aviremia. It can also be transmitted sexually. It is asymptomatic in 80%of people infected, but causes mild to moderate systemic symptoms suchas arthralgia, myalgia, and rash in 20% of people. Additionally it hascaused catastrophic nervous system developmental impairment andmicrocephaly in fetuses and newborns, and Guillain-Barre paralyticsyndrome in some adults. There is at this time no preventative vaccineor direct antiviral treatment. There is no way to reverse thecatastrophic developmental impairment in embryos, fetuses, and newborns.For Guillain Bane Syndrome, only supportive care and immunoglobulintreatment, which is only partially effective, are available.

The inventor has found that mycophenolic acid, derivatives thereof, andcombinations with other agents, such as minocycline, doxycycline,tetracycline, tetracycline derivatives, L-DOPA, and dopamine areeffective in preventing and/or treating certain viruses. In addition,the inventor has found that minocycline, doxycycline, tetracycline,tetracycline derivatives, L-DOPA, dopamine, and combinations thereof areuseful for preventing and/or treating a pathogenic infection in apatient, including, for example, viral infection, bacterial infection,fungal infection, parasitic infection, and combinations thereof.

The inventor has discovered that low guanosine diets can dramaticallyand surprisingly enhance the efficacy of oseltamivir and otherneuraminidase inhibitors for treatment and prevention of viralinfluenza, including pandemic influenza, and other viruses.

The disclosure provides means for prevention and/or treatment ofdangerous pathogenic organisms. The disclosure provides methods andpharmaceutical compositions which are active against an unusually widerange of pathogens and which have lesser toxicity compared to manycurrently available antimicrobial therapies.

-   -   It is shown herein that agents which reduce guanosine are        effective at prevention and mitigation of viral diseases. This        is demonstrated in three different viruses, using animal or in        vitro models: 1. It is demonstrated that a low nucleotide diet        (low guanosine diet) prevents and mitigates West Nile virus        disease, including reducing mortality, in a mouse model; 2. It        is demonstrated below that mycophenolic acid (which reduces        guanosine levels) prevents Zika virus infection in an in vitro        model; and 3. It is demonstrated below that a combination of a        low nucleotide diet (low guanosine diet) and mycophenolic acid,        given before infection and continued, prevents and mitigates        Pandemic Influenza infection in a mouse model.

All references cited herein are incorporated herein by reference intheir entireties.

BRIEF SUMMARY

The method is comprised of two parts. These two parts can beadministered together or sequentially.Part A—Methods for depletion of guanosine-containing nucleosides andnucleotides.Part B—Methods for administering melanin and/or increasing the bodycontent of melanin by modulation of metabolic processes.The parts are briefly summarized below.

Part A—Method for Depletion of Guanosine-Containing Nucleosides andNucleotides.

Guanine is a purine base which is a component of nucleosides such asguanosine and nucleotides such as guanosine monophosphate, guanosinediphosphate, and guanosine triphosphate, cyclic guanosine monophosphate,etc. Guanine is required for replication of most DNA and RNA. It is alsoa component of the ubiquitous G protein receptors, which are involved ininnumerable signaling pathways.

Most microorganisms that cause disease do so partially by replicatingthemselves in high numbers. This includes viruses, bacteria, fungi, andparasites. This requires replication of DNA in bacteria, fungi, andparasites, and replication of DNA or RNA in viruses. In Zika, it is theRNA which replicates.

It has been demonstrated that restriction or complete inhibition ofguanine supplies prevents replication of some viruses and otherpathogenic organisms such as bacteria. This can be accomplished byseveral chemical agents (e.g. mycophenolic acid, tiazofurin,selenazofurin, ribavirin,5-ethinyl-1-β-D-ribofuranosylimidazole-4-carboxamide)) (Neyts, J., andDe Clercq, E. “Mycophenolate Mofetil Strongly Potentiates theAnti-herpesvirus Activity of Acyclovir.” Antiviral research 40 (1998):53-56.). Restriction of guanine supplies is generally not used inmedical treatment of any infectious disease. It should be noted thatearly studies of mycophenolate showed relatively rapid emergence ofbacterial resistance, and perhaps this is the reason why this strategyhas not been adopted. Additionally, it is possible to significantlydeplete a human's supply of guanosine by a novel selective dietrestriction which is described below.

Part B—Methods for Administering Melanin and/or Increasing the BodyContent of Melanin by Modulation of Metabolic Processes.

Melanin is a pigment best known for its ability in human skin to absorbultraviolet radiation from the sun. Melanin has been clearlydemonstrated to have antimicrobial properties which are active againstsome viruses, bacteria, fungi and parasites. Its mechanism of actionseems to be unknown. The best studied melanin in the literature isderived from cuttlefish ink. Cuttlefish is a type of cephalopod. Octopusand squid are also cephalopods and also have inks, which are used as adefense mechanism against predators. The ink contains approximately 15to 20% melanin, about 5% protein and carbohydrates, and the rest iswater.

Human beings also continuously synthesize melanin in the skin andperhaps in the nervous system. Various hormones and other agents havebeen demonstrated to be capable of increasing melanin synthesis inhumans and other mammals. One example is Melanocyte-Stimulating Hormone(MSH).

The present disclosure represents a fundamentally novel strategy indeveloping therapy against Zika virus, other microbes and parasites.Historically, and increasingly so in the recent years, researchers,pharmaceutical companies, and governments devote their efforts towardtargeting single agents or small groups of specific microbes. Forinstance, an enormous amount of resources has appropriately been devotedto fighting the HIV virus. However, as a result, most of the therapiesdeveloped are only active against that single microbe. Similarly, manyof the new antibiotics developed in the last few decades are targeted toa small group of microbes. For instance the cephalosporins weredeveloped specifically against penicillin resistant bacteria. While ofcourse these advances are welcome, the cephalosporins are generally onlyactive against the rather limited organisms against which they weredeveloped.

The present disclosure represents a fundamentally different strategyfrom the historical strategy just described. The present disclosuretargets the Zika virus and other disease-causing microbes includingviruses, bacteria, fungi, and parasites. It does this using agents andmethods with little toxicity compared to existing therapies.

The disclosure provides a method of preventing and/or treating apathogenic infection in patient, the method comprising the steps of:selecting a patient in need of preventing and/or treating a pathogenicinfection; administering to the patient at least one agent whichdepletes guanosine-containing nucleosides and nucleotides; wherein thepathogenic infection is prevented and/or treated in the patient. Thedisclosure provides a method wherein the pathogenic infection isselected from the group consisting of viral infection, bacterialinfection, fungal infection, parasitic infection, and combinationsthereof. The disclosure provides a method, wherein the pathogenicinfection is a viral infection. The disclosure provides a method whereinthe viral infection is selected from the group consisting of Zika virus,Norovirus, Respiratory Syncytial Virus, Influenza, Adenovirus 5, HPV 11,Lassa Fever virus, Powassan virus, Rift Valley virus, and combinationsthereof. The disclosure provides a method, wherein the at least oneagent which depletes guanosine-containing nucleosides and nucleotides isselected from the group consisting of mycophenolate, IMPDH enzymeinhibitors, agents which bind to guanine, or guanosine-containingnucleosides and nucleotides, and combinations thereof.

The disclosure provides a method of preventing and/or treating apathogenic infection in patient, the method comprising the steps of:selecting a patient in need of preventing and/or treating a pathogenicinfection; administering to the patient a diet which depletesguanosine-containing nucleosides and nucleotides; wherein the pathogenicinfection is prevented and/or treated in the patient. The disclosureprovides a method wherein the pathogenic infection is selected from thegroup consisting of viral infection, bacterial infection, fungalinfection, parasitic infection, and combinations thereof. The disclosureprovides a method wherein the pathogenic infection is a viral infection.The disclosure provides a method wherein the viral infection is selectedfrom the group consisting of Zika virus, Norovirus, respiratorysyncytial virus, Influenza, Adenovirus 5, HPV 11, Lassa Fever virus,Powassan virus, Rift Valley virus, and combinations thereof. Thedisclosure provides a method wherein the diet which depletesguanosine-containing nucleosides and nucleotides contains a nucleotidecontent which is selected from the group consisting of about 1000mg/day, of about 750 mg/day, of about 500 mg/day, of about 250 mg/day,of about 100 mg/day, of about 75 mg/day, of about 50 mg/day, and ofabout 25 mg/day of nucleotide. The disclosure provides a method ofadministering to a patient a diet which depletes guanosine-containingnucleosides and nucleotides and an anti-viral agent. The disclosureprovides a method of administering to a patient a diet which depletesguanosine-containing nucleosides and nucleotides and an anti-viral agentwhich is oseltamivir. The disclosure provides a method of preventingand/or treating a pathogenic infection in patient, the method comprisingthe steps of: selecting a patient in need of preventing and/or treatinga pathogenic infection; administering to the patient at least one agentselected from the group consisting of melanin, melanin precursors,melanin derivatives, melanin analogs and related substances, andcombinations thereof; wherein the pathogenic infection is preventedand/or treated in the patient. The disclosure provides a method whereinthe pathogenic infection is selected from the group consisting of viralinfection, bacterial infection, fungal infection, parasitic infection,and combinations thereof. The disclosure provides a method wherein thepathogenic infection is a viral infection. The disclosure provides amethod wherein the viral infection is selected from the group consistingof Zika virus, Norovirus, Respiratory Syncytial Virus, Influenza,Adenovirus 5, HPV 11, Lassa Fever virus, Powassan virus, Rift Valleyvirus, and combinations thereof. The disclosure provides a methodwherein the melanin precursor is selected from the group consisting oftyrosine, 3,4-dihydroxy phenylalanine (dopa), D-dopa, catechol,5-hydroxyindole, tyramine, dopamine, m-aminophenol, o-aminophenol,p-aminophenol, 4-aminocatechol, 2-hydroxyl-1,4-naphthaquinone (henna),4-methyl catechol, 3,4-dihydroxybenzylamine, 3,4-dihydroxybenzoic acid,1,2-dihydroxynaphthalene, gallic acid, resorcinol, 2-chloroaniline,p-chloroanisole, 2-amino-p-cresol, 4,5-dihydroxynaphthalene2,7-disulfonic acid, o-cresol, m-cresol, p-cresol, and combinationsthereof. The disclosure provides a method wherein at least one agentselected from the group consisting of melanin, melanin precursors,melanin derivatives, melanin analogs and related substances, andcombinations thereof is administered in topical form. The disclosureprovides a method of preventing and/or treating a pathogenic infectionin patient, the method comprising the steps of: selecting a patient inneed of preventing and/or treating a pathogenic infection; administeringto the patient at least one agent selected from the group consisting ofmelanin, melanin precursors, melanin derivatives, melanin analogs andrelated substances, and combinations thereof and an anti-viral agent,which may be oseltamivir.

The disclosure provides a pharmaceutical composition comprising at leastone agent selected from the group consisting of melanin, melaninprecursors, melanin derivatives, melanin analogs and related substances,and combinations thereof in a form for topical administration. Thedisclosure provides a pharmaceutical composition comprising at least oneagent selected from the group consisting of melanin, melanin precursors,melanin derivatives, melanin analogs and related substances, andcombinations thereof in a form for topical administration and ananti-viral agent which may be oseltamivir.

The disclosure provides a method of preventing and/or treating apathogenic infection in patient, the method comprising the steps of: (i)selecting a patient in need of preventing and/or treating a pathogenicinfection; (ii) administering to the patient at least one agent whichdepletes guanosine-containing nucleosides and nucleotides; and (iii)prior to, concurrently with, or subsequently to step (ii), administeringto the patient a diet which depletes guanosine-containing nucleosidesand nucleotides; wherein the pathogenic infection is prevented and/ortreated in the patient. The disclosure provides a method wherein thepathogenic infection is selected from the group consisting of viralinfection, bacterial infection, fungal infection, parasitic infection,and combinations thereof. The disclosure provides a method wherein thepathogenic infection is a viral infection. The disclosure provides amethod wherein the viral infection is selected from the group consistingof Zika virus, Norovirus, Respiratory Syncytial Virus, Influenza,Adenovirus 5, HPV 11, Lassa Fever virus, Powassan virus, Rift Valleyvirus, and combinations thereof. The disclosure provides a methodwherein the at least one agent which depletes guanosine-containingnucleosides and nucleotides is selected from the group consisting ofmycophenolate, IMPDH enzyme inhibitors, agents which bind to guanine, orguanosine-containing nucleosides and nucleotides, and combinationsthereof. The disclosure provides a method wherein the diet whichdepletes guanosine-containing nucleosides and nucleotides contains anucleotide content which is selected from the group consisting of about1000 mg/day, of about 750 mg/day, of about 500 mg/day, of about 250mg/day, of about 100 mg/day, of about 75 mg/day, of about 50 mg/day, andof about 25 mg/day of nucleotide.

The disclosure provides a method of preventing and/or treating apathogenic infection in a patient, the method comprising the steps of:selecting a patient in need of preventing and/or treating a pathogenicinfection; administering to the patient at least one first agent whichdepletes guanosine-containing nucleosides and nucleotides; andadministering to the patient at least one second agent selected from thegroup consisting of melanin, melanin precursors, melanin derivatives,melanin analogs and related substances, and combinations thereof;wherein the pathogenic infection is prevented and/or treated in thepatient. The disclosure provides a method wherein the at least one firstagent is administered prior to, concurrently with, or subsequently tothe at least one second agent. The disclosure provides a method whereinthe at least one first agent and at least one second agent are in apharmaceutical composition. The disclosure provides a method wherein theat least one first agent and at least one second agent are in the samedosage form. The disclosure provides a method wherein the second agentis an anti-viral agent, which may be oseltamivir. The disclosureprovides a method wherein the at least one first agent and at least onesecond agent are in separate dosage forms. The disclosure provides amethod wherein the pharmaceutical composition is formulated ormanufactured as a liquid, an elixir, an aerosol, a spray, a powder, atablet, a pill, a capsule, a gel, a geltab, a nanosuspension, ananoparticle, an extended release dosage form, or a topical formulation.The disclosure provides a method wherein the pathogenic infection isselected from the group consisting of viral infection, bacterialinfection, fungal infection, parasitic infection, and combinationsthereof. The disclosure provides a method wherein the pathogenicinfection is a viral infection. The disclosure provides a method whereinthe viral infection is selected from the group consisting of Zika virus,Norovirus, Respiratory Syncytial Virus, Influenza, Adenovirus 5, HPV 11,Lassa Fever virus, Powassan virus, Rift Valley virus, and combinationsthereof. The disclosure provides a method wherein the at least one agentwhich depletes guanosine-containing nucleosides and nucleotides isselected from the group consisting of mycophenolate, IMPDH enzymeinhibitors, agents which bind to guanine, or guanosine-containingnucleosides and nucleotides, and combinations thereof. The disclosureprovides a method wherein the melanin precursor is selected from thegroup consisting of tyrosine, 3,4-dihydroxy phenylalanine (dopa),D-dopa, catechol, 5-hydroxyindole, tyramine, dopamine, m-aminophenol,o-aminophenol, p-aminophenol, 4-aminocatechol,2-hydroxyl-1,4-naphthaquinone (henna), 4-methyl catechol,3,4-dihydroxybenzylamine, 3,4-dihydroxybenzoic acid,1,2-dihydroxynaphthalene, gallic acid, resorcinol, 2-chloroaniline,p-chloroanisole, 2-amino-p-cresol, 4,5-dihydroxynaphthalene2,7-disulfonic acid, o-cresol, m-cresol, p-cresol, and combinationsthereof.

The disclosure provides a pharmaceutical composition comprising: (i) atleast one first agent which depletes guanosine-containing nucleosidesand nucleotides; and (ii) at least one second agent selected from thegroup consisting of melanin, melanin precursors, melanin derivatives,melanin analogs and related substances, and combinations thereof;wherein the pharmaceutical composition further comprises at least onepharmaceutically acceptable excipient. The disclosure provides apharmaceutical composition wherein the at least one agent which depletesguanosine-containing nucleosides and nucleotides is selected from thegroup consisting of mycophenolate, IMPDH enzyme inhibitors, agents whichbind to guanine, or guanosine-containing nucleosides and nucleotides,and combinations thereof. The disclosure provides a pharmaceuticalcomposition wherein the pharmaceutical composition is formulated ormanufactured as a liquid, an elixir, an aerosol, a spray, a powder, atablet, a pill, a capsule, a gel, a geltab, a nanosuspension, ananoparticle, an extended release dosage form, or a topical formulation.The disclosure provides a pharmaceutical composition wherein the atleast one first agent and at least one second agent are in the samedosage form. The disclosure provides a pharmaceutical compositionwherein the at least one first agent and at least one second agent arein separate dosage forms. The disclosure provides a pharmaceuticalcomposition wherein the pharmaceutical composition is formulated ormanufactured as a liquid, an elixir, an aerosol, a spray, a powder, atablet, a pill, a capsule, a gel, a geltab, a nanosuspension, ananoparticle, an extended release dosage form, or a topical formulation.The disclosure provides a pharmaceutical composition wherein thepharmaceutical composition is in a form for topical administration. Thedisclosure provides a pharmaceutical composition comprising: (i) atleast one first agent which depletes guanosine-containing nucleosidesand nucleotides; and (ii) at least one second agent selected from thegroup consisting of melanin, melanin precursors, melanin derivatives,melanin analogs and related substances, and combinations thereof and ananti-viral agent, which may be oseltamivir.

The disclosure provides a pharmaceutical composition comprising: (i) atleast one first agent which depletes guanosine-containing nucleosidesand nucleotides; and (ii) at least one second agent which is ananti-viral agent, which may be oseltamivir.

The disclosure provides a method of preventing and/or treating apathogenic infection in a patient, the method comprising the steps of:selecting a patient in need of preventing and/or treating a pathogenicinfection; administering to the patient at least one first agent whichdepletes guanosine-containing nucleosides and nucleotides; andadministering to the patient at least one second agent selected from thegroup consisting of minocycline, doxycycline, tetracycline, tetracyclinederivatives, L-DOPA, dopamine, and combinations thereof; wherein thepathogenic infection is prevented and/or treated in the patient. Thedisclosure provides a method wherein the at least one agent whichdepletes guanosine-containing nucleosides and nucleotides is selectedfrom the group consisting of mycophenolate, IMPDH enzyme inhibitors,agents which bind to guanine, or guanosine-containing nucleosides andnucleotides, and combinations thereof. The disclosure provides a methodwherein the at least one first agent is administered prior to,concurrently with, or subsequently to the at least one second agent. Thedisclosure provides a method wherein the at least one first agent and atleast one second agent are in a pharmaceutical composition. Thedisclosure provides a method wherein the at least one first agent and atleast one second agent are in the same dosage form. The disclosureprovides a method wherein the at least one first agent and at least onesecond agent are in separate dosage forms. The disclosure provides amethod wherein the pharmaceutical composition is formulated ormanufactured as a liquid, an elixir, an aerosol, a spray, a powder, atablet, a pill, a capsule, a gel, a geltab, a nanosuspension, ananoparticle, an extended release dosage form, or a topical formulation.The disclosure provides a method wherein the pathogenic infection isselected from the group consisting of viral infection, bacterialinfection, fungal infection, parasitic infection, and combinationsthereof. The disclosure provides a method wherein the pathogenicinfection is a viral infection. The disclosure provides a method whereinthe viral infection is selected from the group consisting of Zika virus,Norovirus, Respiratory Syncytial Virus, Influenza, Adenovirus 5, HPV 11,Lassa Fever virus, Powassan virus, Rift Valley virus, and combinationsthereof. The disclosure provides a method wherein the at least one agentwhich depletes guanosine-containing nucleosides and nucleotides isselected from the group consisting of mycophenolate, IMPDH enzymeinhibitors, agents which bind to guanine, or guanosine-containingnucleosides and nucleotides, and combinations thereof. The disclosureprovides a method wherein the melanin precursor is selected from thegroup consisting of tyrosine, 3,4-dihydroxy phenylalanine (dopa),D-dopa, catechol, 5-hydroxyindole, tyramine, dopamine, m-aminophenol,o-aminophenol, p-aminophenol, 4-aminocatechol,2-hydroxyl-1,4-naphthaquinone (henna), 4-methyl catechol,3,4-dihydroxybenzylamine, 3,4-dihydroxybenzoic acid,1,2-dihydroxynaphthalene, gallic acid, resorcinol, 2-chloroaniline,p-chloroanisole, 2-amino-p-cresol, 4,5-dihydroxynaphthalene2,7-disulfonic acid, o-cresol, m-cresol, p-cresol, and combinationsthereof. The disclosure provides a method of preventing and/or treatinga pathogenic infection in a patient, the method comprising the steps of:selecting a patient in need of preventing and/or treating a pathogenicinfection; administering to the patient at least one first agent whichdepletes guanosine-containing nucleosides and nucleotides; andadministering to the patient at least one second agent selected from thegroup consisting of minocycline, doxycycline, tetracycline, tetracyclinederivatives, L-DOPA, dopamine, and combinations thereof, and ananti-viral agent which may be oseltamivir.

The disclosure provides a pharmaceutical composition comprising: (i) atleast one first agent which depletes guanosine-containing nucleosidesand nucleotides; and (ii) at least one second agent selected from thegroup consisting of minocycline, doxycycline, tetracycline, tetracyclinederivatives, L-DOPA, dopamine, and combinations thereof; wherein thepharmaceutical composition further comprises at least onepharmaceutically acceptable excipient. The disclosure provides apharmaceutical composition wherein the at least one agent which depletesguanosine-containing nucleosides and nucleotides is selected from thegroup consisting of mycophenolate, IMPDH enzyme inhibitors, agents whichbind to guanine, or guanosine-containing nucleosides and nucleotides,and combinations thereof. The disclosure provides a pharmaceuticalcomposition wherein the pharmaceutical composition is formulated ormanufactured as a liquid, an elixir, an aerosol, a spray, a powder, atablet, a pill, a capsule, a gel, a geltab, a nanosuspension, ananoparticle, an extended release dosage form, or a topical formulation.The disclosure provides a pharmaceutical composition wherein the atleast one first agent and at least one second agent are in the samedosage form. The disclosure provides a pharmaceutical compositionwherein the at least one first agent and at least one second agent arein separate dosage forms. The disclosure provides a pharmaceuticalcomposition wherein the pharmaceutical composition is formulated ormanufactured as a liquid, an elixir, an aerosol, a spray, a powder, atablet, a pill, a capsule, a gel, a geltab, a nanosuspension, ananoparticle, an extended release dosage form, or a topical formulation.The disclosure provides a pharmaceutical composition wherein thepharmaceutical composition is in a form for topical administration. Thedisclosure provides a pharmaceutical composition comprising: (i) atleast one first agent which depletes guanosine-containing nucleosidesand nucleotides; and (ii) at least one second agent which is anantiviral agent, which may be oseltamivir.

The disclosure provides a method of preventing and/or treating postviralneurological syndromes in a patient, the method comprising the steps of:selecting a patient in need of preventing and/or treating postviralneurological syndrome; administering to the patient at least one agentselected from the group consisting of melanin, melanin precursors,melanin derivatives, melanin analogs, minocycline, doxycycline,tetracycline, tetracycline derivatives, L-DOPA, dopamine, andcombinations thereof; wherein the postviral neurological syndromes isprevented and/or treated in the patient. The disclosure provides amethod wherein the postviral neurological syndromes are as a result ofinfection by a virus selected from the group consisting of Zika virus,Norovirus, Respiratory Syncytial Virus, Influenza, Adenovirus 5, HPV 11,Lassa Fever virus, Powassan virus, Rift Valley virus, and combinationsthereof. The disclosure provides a method wherein at least one agent isadministered in topical form. The disclosure provides a method ofpreventing and/or treating postviral neurological syndromes in apatient, the method comprising the steps of: selecting a patient in needof preventing and/or treating postviral neurological syndrome;administering to the patient at least one agent selected from the groupconsisting of melanin, melanin precursors, melanin derivatives, melaninanalogs, minocycline, doxycycline, tetracycline, tetracyclinederivatives, L-DOPA, dopamine, and combinations thereof, and ananti-viral agent which may be oseltamivir.

The disclosure provides a method of preventing and/or treating apathogenic infection in a patient, the method comprising the steps of:selecting a patient in need of preventing and/or treating a pathogenicinfection; administering to the patient at least one agent selected fromthe group consisting of minocycline, doxycycline, tetracycline,tetracycline derivatives, L-DOPA, dopamine, and combinations thereof;wherein the pathogenic infection is prevented and/or treated in thepatient. The disclosure provides a method wherein the at least one agentis administered prior to, concurrently with, or subsequently to the atleast one second agent. The disclosure provides a method wherein the atleast one agent is in a pharmaceutical composition. The disclosureprovides a method wherein the pharmaceutical composition is formulatedor manufactured as a liquid, an elixir, an aerosol, a spray, a powder, atablet, a pill, a capsule, a gel, a geltab, a nanosuspension, ananoparticle, an extended release dosage form, or a topical formulation.The disclosure provides a method wherein the pathogenic infection isselected from the group consisting of viral infection, bacterialinfection, fungal infection, parasitic infection, and combinationsthereof. The disclosure provides a method wherein the pathogenicinfection is a viral infection. The disclosure provides a method whereinthe viral infection is selected from the group consisting of Zika virus,Norovirus, Respiratory Syncytial Virus, Influenza, Adenovirus 5, HPV 11,Lassa Fever virus, Powassan virus, Rift Valley virus, and combinationsthereof. The disclosure provides a method of preventing and/or treatinga pathogenic infection in a patient, the method comprising the steps of:selecting a patient in need of preventing and/or treating a pathogenicinfection; administering to the patient at least one agent selected fromthe group consisting of minocycline, doxycycline, tetracycline,tetracycline derivatives, L-DOPA, dopamine, and combinations thereof,and an anti-viral agent which may be oseltamivir.

The disclosure provides a pharmaceutical composition comprising: atleast one agent selected from the group consisting of minocycline,doxycycline, tetracycline, tetracycline derivatives, L-DOPA, dopamine,and combinations thereof; wherein the pharmaceutical composition furthercomprises at least one pharmaceutically acceptable excipient. Thedisclosure provides a pharmaceutical composition wherein thepharmaceutical composition is formulated or manufactured as a liquid, anelixir, an aerosol, a spray, a powder, a tablet, a pill, a capsule, agel, a geltab, a nanosuspension, a nanoparticle, an extended releasedosage form, or a topical formulation. The disclosure provides apharmaceutical composition wherein the pharmaceutical composition isformulated or manufactured as a liquid, an elixir, an aerosol, a spray,a powder, a tablet, a pill, a capsule, a gel, a geltab, ananosuspension, a nanoparticle, an extended release dosage form, or atopical formulation. The disclosure provides a pharmaceuticalcomposition wherein the pharmaceutical composition is in a form fortopical administration. The disclosure provides a pharmaceuticalcomposition comprising: at least one agent selected from the groupconsisting of minocycline, doxycycline, tetracycline, tetracyclinederivatives, L-DOPA, dopamine, and combinations thereof, and ananti-viral agent which may be oseltamivir.

The disclosure provides a pharmaceutical composition comprising: atleast one agent selected from the group consisting of minocycline,doxycycline, tetracycline, tetracycline derivatives, L-DOPA, dopamine,and combinations thereof; wherein the pharmaceutical composition furthercomprises at least one second agent which is an anti-viral agent, whichmay be oseltamivir.

The disclosure provides a method of preventing and/or treating postviralneurological syndromes in a patient, the method comprising the steps of:selecting a patient in need of preventing and/or treating postviralneurological syndrome; administering to the patient at least one agentselected from the group consisting of minocycline, doxycycline,tetracycline, tetracycline derivatives, L-DOPA, dopamine, andcombinations thereof; wherein the postviral neurological syndrome isprevented and/or treated in the patient. The disclosure provides amethod wherein the postviral neurological syndromes are as a result ofinfection by a virus selected from the group consisting of Zika virus,Norovirus, Respiratory Syncytial Virus, Influenza, Adenovirus 5, HPV 11,Lassa Fever virus, Powassan virus, Rift Valley virus, and combinationsthereof. The disclosure provides a method wherein at least one agent isadministered in topical form. The disclosure provides a method ofpreventing and/or treating postviral neurological syndromes in apatient, the method comprising the steps of: selecting a patient in needof preventing and/or treating postviral neurological syndrome;administering to the patient at least one agent selected from the groupconsisting of minocycline, doxycycline, tetracycline, tetracyclinederivatives, L-DOPA, dopamine, and combinations thereof, and ananti-viral agent which may be oseltamivir.

The disclosure provides a method of preventing a viral infection in apatient, the method comprising the steps of: selecting a patient in needof preventing a viral infection; administering to the patient at leastone agent which depletes guanosine-containing nucleosides andnucleotides; wherein the viral infection is a flaviviridae virus, andfurther wherein the viral infection is prevented in the patient. Thedisclosure provides a method wherein the flaviviridae virus is selectedfrom the group consisting of Absettarov virus, Alfuy virus Apoi virusAroa virus, Bagaza virus Border disease virus Bouboui virus Bovinediarrhea virus Bussuquara virus Bukalasa bat virus, Dengue virus group,Hog cholera virus, Zika virus, Yellow fever virus; Dengue virus; St.Louis encephalitis virus; Japanese encephalitis virus; Tick-borneencephalitis virus; Omsk hemorrhagic fever virus; Al Khumra virus;Kyasanur Forest disease virus; Louping ill virus; West Nile virus;Kunjin virus; Murray Valley fever virus; Powassan virus; Hepatitis Cvirus; Hepatitis G virus, and combinations thereof. The disclosureprovides a method wherein the at least one agent which depletesguanosine-containing nucleosides and nucleotides is selected from thegroup consisting of mycophenolate, IMPDH enzyme inhibitors, agents whichbind to guanine, or guanosine-containing nucleosides and nucleotides,and combinations thereof.

The disclosure provides a method of preventing a viral infection in apatient, the method comprising the steps of: selecting a patient in needof preventing a viral infection; administering to the patient a dietwhich depletes guanosine-containing nucleosides and nucleotides; whereinthe viral infection is a flaviviridae virus, and further wherein theviral infection is prevented in the patient. The disclosure provides amethod wherein the flaviviridae virus is selected from the groupconsisting of Absettarov virus, Alfuy virus Apoi virus Aroa virus,Bagaza virus Border disease virus Bouboui virus Bovine diarrhea virusBussuquara virus Bukalasa bat virus, Dengue virus group, Hog choleravirus, Zika virus, Yellow fever virus; Dengue virus; St. Louisencephalitis virus; Japanese encephalitis virus; Tick-borne encephalitisvirus; Omsk hemorrhagic fever virus; Al Khumra virus; Kyasanur Forestdisease virus; Louping ill virus; West Nile virus; Kunjin virus; MurrayValley fever virus; Powassan virus; Hepatitis C virus; Hepatitis Gvirus, and combinations thereof. The disclosure provides a methodwherein the diet which depletes guanosine-containing nucleosides andnucleotides contains a nucleotide content which is selected from thegroup consisting of about 1000 mg/day, of about 750 mg/day, of about 500mg/day, of about 250 mg/day, of about 100 mg/day, of about 75 mg/day, ofabout 50 mg/day, and of about 25 mg/day of nucleotide.

The disclosure provides a method of preventing a viral infection in apatient, the method comprising the steps of: (i) selecting a patient inneed of preventing a viral infection; (ii) administering to the patientat least one agent which depletes guanosine-containing nucleosides andnucleotides; and (iii) prior to, concurrently with, or subsequently tostep (ii), administering to the patient a diet which depletesguanosine-containing nucleosides and nucleotides; wherein the virus is aflaviviridae virus, and further wherein the viral infection is preventedin the patient. The disclosure provides a method wherein theflaviviridae virus is selected from the group consisting of Absettarovvirus, Alfuy virus Apoi virus Aroa virus, Bagaza virus Border diseasevirus Bouboui virus Bovine diarrhea virus Bussuquara virus Bukalasa batvirus, Dengue virus group, Hog cholera virus, Zika virus, Yellow fevervirus; Dengue virus; St. Louis encephalitis virus; Japanese encephalitisvirus; Tick-borne encephalitis virus; Omsk hemorrhagic fever virus; AlKhumra virus; Kyasanur Forest disease virus; Louping ill virus; WestNile virus; Kunjin virus; Murray Valley fever virus; Powassan virus;Hepatitis C virus; Hepatitis G virus, and combinations thereof. Thedisclosure provides a method wherein the at least one agent whichdepletes guanosine-containing nucleosides and nucleotides is selectedfrom the group consisting of mycophenolate, IMPDH enzyme inhibitors,agents which bind to guanine, or guanosine-containing nucleosides andnucleotides, and combinations thereof. The disclosure provides a methodwherein the diet which depletes guanosine-containing nucleosides andnucleotides contains a nucleotide content which is selected from thegroup consisting of about 1000 mg/day, of about 750 mg/day, of about 500mg/day, of about 250 mg/day, of about 100 mg/day, of about 75 mg/day, ofabout 50 mg/day, and of about 25 mg/day of nucleotide.

The disclosure provides a method of preventing a viral infection in apatient, the method comprising the steps of: selecting a patient in needof preventing a viral infection; administering to the patient at leastone agent which depletes guanosine-containing nucleosides andnucleotides; wherein the viral infection is a respiratory virus, andfurther wherein the viral infection is prevented in the patient. Thedisclosure provides a method wherein the respiratory virus is selectedfrom the group consisting of Influenza virus type A, Influenza A H3N2;Influenza A H5N1 (low path); Influenza B (Victoria); Influenza B(Yamagata); Parainfluenza virus-3; Rhinovirus-14; Influenza A H7N9virus; Influenza A H5N1 (high path), Adenoviruses, Avian influenza,Measles, Parainfluenza virus, Respiratory syncytial virus (RSV),Rhinoviruses, SARS coronavirus, and combinations thereof. The disclosureprovides a method wherein the at least one agent which depletesguanosine-containing nucleosides and nucleotides is selected from thegroup consisting of mycophenolate, IMPDH enzyme inhibitors, agents whichbind to guanine, or guanosine-containing nucleosides and nucleotides,and combinations thereof.

The disclosure provides a method of preventing a viral infection in apatient, the method comprising the steps of: selecting a patient in needof preventing a viral infection; administering to the patient a dietwhich depletes guanosine-containing nucleosides and nucleotides; whereinthe viral infection is a respiratory virus, and further wherein theviral infection is prevented in the patient. The disclosure provides amethod wherein the respiratory virus is selected from the groupconsisting of Influenza virus type A, Influenza A H3N2; Influenza A H5N1(low path); Influenza B (Victoria); Influenza B (Yamagata);Parainfluenza virus-3; Rhinovirus-14; Influenza A H7N9 virus; InfluenzaA H5N1 (high path), Adenoviruses, Avian influenza, Measles,Parainfluenza virus, Respiratory syncytial virus (RSV), Rhinoviruses,SARS coronavirus, and combinations thereof. The disclosure provides amethod wherein the diet which depletes guanosine-containing nucleosidesand nucleotides contains a nucleotide content which is selected from thegroup consisting of about 1000 mg/day, of about 750 mg/day, of about 500mg/day, of about 250 mg/day, of about 100 mg/day, of about 75 mg/day, ofabout 50 mg/day, and of about 25 mg/day of nucleotide.

The disclosure provides a method of preventing a viral infection in apatient, the method comprising the steps of: (i) selecting a patient inneed of preventing a viral infection; (ii) administering to the patientat least one agent which depletes guanosine-containing nucleosides andnucleotides; and (iii) prior to, concurrently with, or subsequently tostep (ii), administering to the patient a diet which depletesguanosine-containing nucleosides and nucleotides; wherein the viralinfection is a respiratory virus, and further wherein the viralinfection is prevented in the patient. The disclosure provides a methodwherein the respiratory virus is selected from the group consisting ofInfluenza virus type A, Influenza A H3N2; Influenza A H5N1 (low path);Influenza B (Victoria); Influenza B (Yamagata); Parainfluenza virus-3;Rhinovirus-14; Influenza A H7N9 virus; Influenza A H5N1 (high path),Adenoviruses, Avian influenza, Measles, Parainfluenza virus, Respiratorysyncytial virus (RSV), Rhinoviruses, SARS coronavirus, and combinationsthereof. The disclosure provides a method wherein the at least one agentwhich depletes guanosine-containing nucleosides and nucleotides isselected from the group consisting of mycophenolate, IMPDH enzymeinhibitors, agents which bind to guanine, or guanosine-containingnucleosides and nucleotides, and combinations thereof. The disclosureprovides a method wherein the diet which depletes guanosine-containingnucleosides and nucleotides contains a nucleotide content which isselected from the group consisting of about 1000 mg/day, of about 750mg/day, of about 500 mg/day, of about 250 mg/day, of about 100 mg/day,of about 75 mg/day, of about 50 mg/day, and of about 25 mg/day ofnucleotide.

The disclosure provides a method of preventing a viral infection in apatient, the method comprising the steps of: selecting a patient in needof preventing a viral infection; administering to the patient at leastone agent which depletes guanosine-containing nucleosides andnucleotides; further wherein the viral infection is prevented in thepatient. The disclosure provides a method wherein the virus which causesthe viral infection is selected from the group consisting ofParvoviridae; Papovaviridae, Human papilloma virus (HPV); BKpolyomavirus; JC polyomavirus); Adenoviridae (Adenovirus, types 40 and41); Herpesviridae (simplex virus type 1 (HHV-1); Herpes simplex virustype 2 (HHV-2); Macacine herpesvirus 1; Varicella-zoster virus;Epstein-Barr virus; Cytomegalovirus); Human Herpesvirus 6; HHV-7;Kaposi's sarcoma-associated herpesvirus; Hepadnaviridae, Hepatitis Bvirus; Poxviridae (Smallpox (Variola major); Alastrim (Variola minor);Vaccinia; Cowpox; Monkeypox; Goat pox, pseudocowpox virus, bovinepapular stomatitis virus, tanapox, volepox and related pox viruses suchas avipox, buffalopox, racoonpox, squirrelpox, etc.); Molluscumcontagiosum; Picornaviridae (Polio virus; Coxsackie A virus; CoxsackieB; virus; Foot and mouth disease; ECHO virus; Hepatitis A virus;Rhinovirus); Astroviridae; Caliciviridae (Norwalk virus; Norovirus;Sapoviruses; Hepatitis E virus); Reoviridae (Rotavirus); Togaviridae(Alpha viruses; Western equine encephalitis (WEE) virus; Eastern equineencephalitis (EEE) virus; Venezuelan equine encephalitis (VEE) virus;Chikungunya virus; Rubivirus (rubella)); Flaviviridae (Yellow fevervirus; Dengue virus; St. Louis encephalitis virus; Japanese encephalitisvirus; Tick-borne encephalitis virus; Omsk hemorrhagic fever virus; AlKhumra virus; Kyasanur Forest disease virus; Louping ill virus; WestNile virus; Kunjin virus; Murray Valley fever virus; Powassan virus;Hepatitis C virus; Hepatitis G virus); Coronoviridae (Respiratoryillness (cold); Severe Acute Respiratory Syndrom)-corona virus(SARS-CoV)); Bunyaviridae (California encephalitis virus; La Crossevirus; Rift Valley fever virus; Phleboviruses; Sandfly fever virus;Nairovirus; Hantavirus); Orthomyxoviridae (Influenza virus (types A, B &C); Paramyxoviridae (Parainfluenza virus; Respiratory syncytial virus(RSV); Hendra virus disease (formerly equine morbillivirus); Nipah virusencephalitis; Mumps Measles; Newcastle disease virus); Rhabdoviridae(Rabies virus); Filoviridae (Marburg virus (acute hemorrhagic fever);Ebola virus (acute hemorrhagic fever)); Arenaviridae (Lymphocyticchoriomeningitis virus; Lassa fever virus; Lujo virus; Chapare virus;Junin virus; Machupo virus; Guanarito virus; Sabia virus); Retroviridae(Human Immunodeficiency virus (HIV) types I and II; Human T-cellleukemia virus (HLTV) type I; Human T-cell leukemia virus (HLTV) typeII; Spumaviruses; Xenotropic murine leukemia virus-related (XMRV), andcombinations thereof. The disclosure provides a method wherein the atleast one agent which depletes guanosine-containing nucleosides andnucleotides is selected from the group consisting of mycophenolate,IMPDH enzyme inhibitors, agents which bind to guanine, orguanosine-containing nucleosides and nucleotides, and combinationsthereof.

The disclosure provides a method of preventing a viral infection in apatient, the method comprising the steps of: selecting a patient in needof preventing a viral infection; administering to the patient a dietwhich depletes guanosine-containing nucleosides and nucleotides; furtherwherein the viral infection is prevented in the patient. The disclosureprovides a method wherein the virus which causes the viral infection isselected from the group consisting of Parvoviridae; Papovaviridae, Humanpapilloma virus (HPV); BK polyomavirus; JC polyomavirus); Adenoviridae(Adenovirus, types 40 and 41); Herpesviridae (simplex virus type 1(HHV-1); Herpes simplex virus type 2 (HHV-2); Macacine herpesvirus 1;Varicella-zoster virus; Epstein-Barr virus; Cytomegalovirus); HumanHerpesvirus 6; HHV-7; Kaposi's sarcoma-associated herpesvirus;Hepadnaviridae, Hepatitis B virus; Poxviridae (Smallpox (Variola major);Alastrim (Variola minor); Vaccinia; Cowpox; Monkeypox; Goat pox,pseudocowpox virus, bovine papular stomatitis virus, tanapox, volepoxand related pox viruses such as avipox, buffalopox, racoonpox,squirrelpox, etc.); Molluscum contagiosum; Picornaviridae (Polio virus;Coxsackie A virus; Coxsackie B; virus; Foot and mouth disease; ECHOvirus; Hepatitis A virus; Rhinovirus); Astroviridae; Caliciviridae(Norwalk virus; Norovirus; Sapoviruses; Hepatitis E virus); Reoviridae(Rotavirus); Togaviridae (Alpha viruses; Western equine encephalitis(WEE) virus; Eastern equine encephalitis (EEE) virus; Venezuelan equineencephalitis (VEE) virus; Chikungunya virus; Rubivirus (rubella));Flaviviridae (Yellow fever virus; Dengue virus; St. Louis encephalitisvirus; Japanese encephalitis virus; Tick-borne encephalitis virus; Omskhemorrhagic fever virus; Al Khumra virus; Kyasanur Forest disease virus;Louping ill virus; West Nile virus; Kunjin virus; Murray Valley fevervirus; Powassan virus; Hepatitis C virus; Hepatitis G virus);Coronoviridae (Respiratory illness (cold); Severe Acute RespiratorySyndrom)-corona virus (SARS-CoV)); Bunyaviridae (California encephalitisvirus; La Crosse virus; Rift Valley fever virus; Phleboviruses; Sandflyfever virus; Nairovirus; Hantavirus); Orthomyxoviridae (Influenza virus(types A, B & C); Paramyxoviridae (Parainfluenza virus; Respiratorysyncytial virus (RSV); Hendra virus disease (formerly equinemorbillivirus); Nipah virus encephalitis; Mumps Measles; Newcastledisease virus); Rhabdoviridae (Rabies virus); Filoviridae (Marburg virus(acute hemorrhagic fever); Ebola virus (acute hemorrhagic fever));Arenaviridae (Lymphocytic choriomeningitis virus; Lassa fever virus;Lujo virus; Chapare virus; Junin virus; Machupo virus; Guanarito virus;Sabia virus); Retroviridae (Human Immunodeficiency virus (HIV) types Iand II; Human T-cell leukemia virus (HLTV) type I; Human T-cell leukemiavirus (HLTV) type II; Spumaviruses; Xenotropic murine leukemiavirus-related (XMRV), and combinations thereof. The disclosure providesa method wherein the diet which depletes guanosine-containingnucleosides and nucleotides contains a nucleotide content which isselected from the group consisting of about 1000 mg/day, of about 750mg/day, of about 500 mg/day, of about 250 mg/day, of about 100 mg/day,of about 75 mg/day, of about 50 mg/day, and of about 25 mg/day ofnucleotide.

The disclosure provides a method of preventing a viral infection in apatient, the method comprising the steps of: (i) selecting a patient inneed of preventing a viral infection; (ii) administering to the patientat least one agent which depletes guanosine-containing nucleosides andnucleotides; and (iii) prior to, concurrently with, or subsequently tostep (ii), administering to the patient a diet which depletesguanosine-containing nucleosides and nucleotides; wherein the viralinfection is prevented in the patient. The disclosure provides a methodwherein the virus which causes the viral infection is selected from thegroup consisting of Parvoviridae; Papovaviridae, Human papilloma virus(HPV); BK polyomavirus; JC polyomavirus); Adenoviridae (Adenovirus,types 40 and 41); Herpesviridae (simplex virus type 1 (HHV-1); Herpessimplex virus type 2 (HHV-2); Macacine herpesvirus 1; Varicella-zostervirus; Epstein-Barr virus; Cytomegalovirus); Human Herpesvirus 6; HHV-7;Kaposi's sarcoma-associated herpesvirus; Hepadnaviridae, Hepatitis Bvirus; Poxviridae (Smallpox (Variola major); Alastrim (Variola minor);Vaccinia; Cowpox; Monkeypox; Goat pox, pseudocowpox virus, bovinepapular stomatitis virus, tanapox, volepox and related pox viruses suchas avipox, buffalopox, racoonpox, squirrelpox, etc.); Molluscumcontagiosum; Picornaviridae (Polio virus; Coxsackie A virus; CoxsackieB; virus; Foot and mouth disease; ECHO virus; Hepatitis A virus;Rhinovirus); Astroviridae; Caliciviridae (Norwalk virus; Norovirus;Sapoviruses; Hepatitis E virus); Reoviridae (Rotavirus); Togaviridae(Alpha viruses; Western equine encephalitis (WEE) virus; Eastern equineencephalitis (EEE) virus; Venezuelan equine encephalitis (VEE) virus;Chikungunya virus; Rubivirus (rubella)); Flaviviridae (Yellow fevervirus; Dengue virus; St. Louis encephalitis virus; Japanese encephalitisvirus; Tick-borne encephalitis virus; Omsk hemorrhagic fever virus; AlKhumra virus; Kyasanur Forest disease virus; Louping ill virus; WestNile virus; Kunjin virus; Murray Valley fever virus; Powassan virus;Hepatitis C virus; Hepatitis G virus); Coronoviridae (Respiratoryillness (cold); Severe Acute Respiratory Syndrom)-corona virus(SARS-CoV)); Bunyaviridae (California encephalitis virus; La Crossevirus; Rift Valley fever virus; Phleboviruses; Sandfly fever virus;Nairovirus; Hantavirus); Orthomyxoviridae (Influenza virus (types A, B &C); Paramyxoviridae (Parainfluenza virus; Respiratory syncytial virus(RSV); Hendra virus disease (formerly equine morbillivirus); Nipah virusencephalitis; Mumps Measles; Newcastle disease virus); Rhabdoviridae(Rabies virus); Filoviridae (Marburg virus (acute hemorrhagic fever);Ebola virus (acute hemorrhagic fever)); Arenaviridae (Lymphocyticchoriomeningitis virus; Lassa fever virus; Lujo virus; Chapare virus;Junin virus; Machupo virus; Guanarito virus; Sabia virus); Retroviridae(Human Immunodeficiency virus (HIV) types I and II; Human T-cellleukemia virus (HLTV) type I; Human T-cell leukemia virus (HLTV) typeII; Spumaviruses; Xenotropic murine leukemia virus-related (XMRV), andcombinations thereof. The disclosure provides a method wherein the atleast one agent which depletes guanosine-containing nucleosides andnucleotides is selected from the group consisting of mycophenolate,IMPDH enzyme inhibitors, agents which bind to guanine, orguanosine-containing nucleosides and nucleotides, and combinationsthereof. The disclosure provides a method wherein the diet whichdepletes guanosine-containing nucleosides and nucleotides contains anucleotide content which is selected from the group consisting of about1000 mg/day, of about 750 mg/day, of about 500 mg/day, of about 250mg/day, of about 100 mg/day, of about 75 mg/day, of about 50 mg/day, andof about 25 mg/day of nucleotide.

The disclosure provides for the use of the compositions of thedisclosure for the production of a medicament for preventing and/ortreating the indications as set forth herein.

In accordance with a further embodiment, the present disclosure providesa use of the pharmaceutical compositions described above, in an amounteffective for use in a medicament, and most preferably for use as amedicament for treating a disease or disorder, for example, as set forthin herein, in a subject.

In accordance with yet another embodiment, the present disclosureprovides a use of the pharmaceutical compositions described above, andat least one additional therapeutic agent, in an amount effective foruse in a medicament, and most preferably for use as a medicament fortreating a disease or disorder associated with disease, for example, asset forth herein, in a subject.

The disclosure provides a method for treating and/or preventing adisease or condition as set forth herein in a patient, wherein saidmethod comprises: selecting a patient in need of treating and/orpreventing said disease or condition as set forth herein; administeringto the patient a composition of the disclosure in a therapeuticallyeffective amount, thereby treating and/or preventing said disease insaid patient.

DETAILED DESCRIPTION OF THE INVENTION

In order to provide a clear and consistent understanding of thespecification and claims, including the scope given to such terms, thefollowing definitions are provided:

To the extent that the term “include,” “have,” or the like is used inthe description or the claims, such term is intended to be inclusive ina manner similar to the term “comprise” as “comprise” is interpretedwhen employed as a transitional word in a claim.

The word “exemplary” is used herein to mean “serving as an example,instance, or illustration.” Any embodiment described herein as“exemplary” is not necessarily to be construed as preferred oradvantageous over other embodiments.

TAMIFLU® as available on the market comprises oseltamivir phosphate,which is a pro-drug of the active metabolite oseltamivir carboxylate,and is specifically adapted for oral administration. Where intranasaladministration is intended according to the present disclosure theactive form oseltamivir carboxylate may be used instead of the phosphatepro-drug form. Thus, the term “oseltamivir” as used herein refers toeither oseltamivir carboxylate or oseltamivir phosphate, unlessexplicitly stated otherwise or unless a different meaning is derivablefrom the disclosure. The antiviral agent may be selected from but is notlimited to the group consisting of zanamivir, oseltamivir, peramivir andlaninamivir. Antiviral agents may also include, but are not limited to,the following: acemannan; alovudine; alvircept sudotox; aranotin;arildone; atevirdine mesylate; avridine, carbovir, cipamfylline;clevadine, crixivan, cytarabine; desciclovir; dideoxyinosine,dideoxycytidine, disoxaril, edoxudine; enfuvirtide, entecavir,enviradene; enviroxime; famciclovir; famotine; fiacitabine; fialuridine;floxuridine, fosarilate; fosfonet, gancyclovir, kethoxal; levovirin,lobucavir; lopinovir, memotine, methisazone; moroxydine, oseltamivir,pirodavir, pleconaril, podophyllotoxin, rimantadine, sequanavir,somantadine, sorivudine, stallimycine, statolon; tilorone; tromantadine,valacyclovir, viramidine, viroxime, xenazoic acid, zalcitabine; zerit,zinviroxime, pyridine, α-methyl-1-adamantanemethylamine,hydroxy-ethoxymethylguanine, adamantanamine, 5-iodo-2′-deoxyuridine,trifluorothymidine, adenine arabinoside, 2′,3′-dideoxynucleosides suchas 2′,3′-didoxycytidine, 2′,3′-dideoxyadenosine, 2′,3′-didoxyinosine,2′,3′-didehydrothymidine, co-trimoxazole, 9-[2-(R)-[[bis[Risopropoxy-carbonyl)oxy]-methoxy]phosphinoyl]methoxy]pro-pyl]adenine,(R)-9-[2-(phosphonomethoxy)-propyl]adenine, tenofivir disoproxil, TATinhibitors such as 7-chloro-5-(2-pyrryl)-3H-1,4-benzodiazepin-2(H)-one.Suitable dosage of the antiviral agent for administration may range fromabout 0.1 μg/day to about 2 g/day, from about 1 μg/day to about 1 g/day,from about 5 μg/day to about 500 mg/day, from about 10 m/day to about300 mg/day, or from about 1 mg/day to about 200 mg/day.

Administration: The application or delivery of a drug to a mammal inneed of the drug. This term is intended to include any means ofadministration which accomplishes the application or delivery of thedrug (i. e., topical, oral, aerosol, suppository, parenteral, e. g.,intravenous, intramuscular, subcutaneous injection, e. g., into thetissue, intraperitoneally and the like). The term is also intended toinclude any means necessary to accomplish such administration. The termis further intended to include the in vivo production of a drug oraggregation of a drug moderated by another substance such as an enzyme(tyrosinase) or enzyme gene (tyrosinase gene) to moderate production ofa drug (melanin) or its precursors, or a concentrating hormone (MCH)subcutaneously to moderate drug (melanin) concentration.

Treatment: Treatment is defined as administration to a mammal sufferingfrom infections or burns or administration to a mammal at risk for suchinfections.

Melanin: Melanins are polymers produced by polymerization of reactiveintermediates. The polymerization mechanisms include but are not limitedto autoxidation, enzyme catalyzed polymerization and free radialinitiated polymerization. The reactive intermediates are producedchemically or enzymatically from precursors. Suitable enzymes include,but are not limited to peroxidases and catalases, polyphenol oxidases,tyrosinases, tyrosine hydroxylases or lactases. The precursors which areconnected to the reactive intermediates are hydroxylated aromaticcompounds. Suitable hydroxylated aromatic compounds include, but are notlimited to 1) phenols, polyphenols, aminophenols and thiophenols ofaromatic or polycyclicaromatic hydrocarbons, including but not limitedto phenol, tyrosine, pyrogallol, 3-aminotyrosine, thiophenol and. alpha.-naphthol; 2) phenols, polyphenols, aminophenols, and thiophenols ofaromatic heterocyclic or heteropolycyclic hydrocarbons such as but notlimited to 2-hydroxypyrrole, 2-pyrazole, 4-hydroxypyridine,8-hydroxyquinoline, and 4, 5-dihydroxybenzothiazole. The term melaninincludes naturally occurring melanins which are usually high molecularweight polymers and low molecular weight polymers as well as melaninanalogs as defined below. Naturally occurring melanin includeseumelanins, phaeomelanins, neuromelanins and allomelanins. The termmelanin is also intended to include trichochromes when used hereafter.The term “melanin” is further intended to include melanin, melaninprecursors, melanin analogs, melanin variants and melanin derivativesunless the context dictates otherwise.

Melanin Analog: Melanin in which a structural feature that occurs innaturally occurring or enzymatically produced melanins is replaced by anunusual substituent divergent from substituents traditionally present inmelanin. An example of an unusual substituent is selinium in place ofsulfur, such as selinocysteine.

Melanin Derivative: This term is intended to include any derivative ofmelanin which is capable of being converted to either melanin or asubstance having melanin activity. An example of a melanin derivative ismelanin attached to a dihydrotrigonelline carrier such as described inBodor, N., Ann. N. Y. Acad. Sci. 507,289 (1987) to enable the melanin tocross the blood-brain barrier. The term melanin derivatives is alsointended to include chemical derivatives of melanin, such as anesterified melanin.

Melanin Variant: Melanin variants include various subsets of melaninsubstances that occur as families of related materials. Included inthese subsets, but not limited thereto, are: (1) Naturally occurringmelanins produced by whole cells that vary in their chemical andphysical characteristics; (2) Enzymatically produced melanins preparedfrom a variety of precursor substrates under diverse reactionconditions; (3) Melanin analogs in which a structural feature thatoccurs in (1) or (2) above is replaced by an unusual substituentdivergent from the traditional; and (4) Melanin derivatives in which asubstituent in a melanin produced in (1), (2) or (3) above is furtheraltered by chemical or enzymatic means.

Tyrosinase: An enzyme which, in mammals, catalyzes: (a) thehydroxylation of tyrosine to dopa (3,4-dihydroxyphenylalanine); (b) theoxidation of dopa to dopaquinone; and (c) may catalyze the oxidation of5,6-dihydroxyindole to indole-5,6-quinone. All of these reactionscatalyzed by tyrosinase take place in the biosynthetic pathway whichproduces melanin. Tyrosinase is most commonly found in a glycosylatedform in vivo.

Melanin Concentrating Hormone: Melanin concentrating hormone (MCH) is apeptide which has been isolated from fish pituitary glands,characterized and synthesized (Kawauchi, H. et al., Nature 305,321(1983)). MCH has also been localized by immunohistochemistry in thebrain and pituitary gland of salmon, frogs and rats (Baker, B. J. etal., Gen. Comp. Endocrinol. 50,1423 (1983), Naito, N. et al., Neurosci.Lett. 70, 81 (1986), Skotfitsch, G. et al., Proc. Natl. Acad. Sci. USA83, 1528 (1986) and Zamir, N. et al., Brain Research 373, 240 (1986)).

A mammalian MCH-like substance has been detected using salmon MCHantiserum directed against salmon MCH by radioimmunoassay andimmunohistochemistry (Zamir, N. et al., Proc. Natl. Acad. Sci. USA,supra). This mammalian MCH exhibits distinct chromatographic propertieson both Reversed Phase High Performance Liquid Chromatography (RP-HPLC)and gel chromatography when compared to the fish enzyme. Id. Thepersistence of this mammalian MCH in the mammalianhypothalamo-neurohypophyseal system suggests a role for MCH in posteriorpituitary function, such as the regulation of food and water intake. Id.Other functions of this mammalian MCH peptide have also been suggested.For example, due to the identification of MCH fibers in the human medianeminence and pituitary stalk, it has been suggested that the peptidecauses the aggregation or concentration of melanin in cells of thecentral nervous system and may be involved in the regulation of anteriorpituitary function (Pelletier, G. et al., Brain Research 423, 247(1987)). Furthermore, Sekiya, K. et al. (Neuroscience 25, 925, 1988)suggest that MCH may act as a neurotransmitter and/or neuromodulator inthe central nervous system or may regulate the pituitary portal-bloodsystem and/or the neurosecretory system in mammals.

Melanin: Naturally occurring melanins include eumelanins, phaeomelanins,neuromelanins and allomelanins. Trichochromes which are low molecularweight polymers derived from the oxidation of tyrosine are alsoconsidered melanins for the purpose of this disclosure.

Melanins and melanin variants are as defined above. Melanin variants areconsidered melanins for the purpose of this disclosure unless thecontext indicates otherwise.

The patient or subject to be treated may be any animal or human. Thesubject is preferably mammalian. In some embodiments the subject is ahuman. In other embodiments the subject is an animal, more preferably anon-human mammal. The non-human mammal may be a domestic pet, or animalkept for commercial purposes, e.g. a race horse, or farming livestocksuch as pigs, sheep or cattle. As such the disclosure may haveveterinary applications. Non-human mammals include rabbits, guinea pigs,rats, mice or other rodents (including any animal in the orderRodentia), cats, dogs, pigs, sheep, goats, cattle (including cows or anyanimal in the order Bos), horse (including any animal in the orderEquidae), donkey, and non-human primates. The subject may be male orfemale. The subject may be a patient.

Part A—Methods for Depletion of Guanosine-Containing Nucleosides andNucleotides; Specialized Diets and Dietary Program for Treatment of Zikaand Other Viral Diseases

Part A can be implemented using either or both of the followingapproaches.

Part A1—Administering agents which depletes guanosine-containingnucleosides and nucleotides.

One approach is that of administering agents (e.g. chemicals, ormolecules such as immunoglobulins) that have the effect of reducing thecontent of guanosine-containing nucleosides and nucleotides inparticular tissues or the whole body. One way to do this, for example,is that used by mycophenolate and similar compounds that inhibit theIMPDH enzyme, which is necessary for the production of guanosinemonophosphate, a key intermediate in the nucleotide synthesis pathway.Another approach would be to administer agents which bind to guanine, orguanosine-containing nucleosides and nucleotides, to reduce theiravailability.

Part A2—Dietary restriction of guanosine intake and substances used bythe body to synthesize guanosine. We describe below specialized dietsthat we have constructed and used which specifically reduce the dietaryintake of guanosine.

It utilizes diets which are low in nucleic acids and their componentsbut which are not nucleotide-free. The diets contain approximately 3% to50% of the amount by weight of nucleotides seen in the normal westerndiet (2000 mg/day, from Ekelman, K. Disodium 5′Guanylate and Disodium5′-Inosate. WHO Food Additives Series, No. 32 (1993), and preferably10%-40%. The percentage of nucleotides, nucleosides, and other nucleicacid components in specific foods has been published by differentresearchers using various analytic techniques over the years (e.g.Lassek, E, and A Montag. “Nucleic Acid Components in Carbohydrate-richFood.” Zeitschrift für Lebensmittel-Untersuchung und -Forschung 190, no.1 (1990): doi:1689090; Souci, S W, W Fachmann, H Kraut, Eva Kirchhoff,and Forschungsanstalt Forschungsanstalt für Deutsche. Food Compositionand Nutrition Tables. Stuttgart: Medpharm, 2008; Brulé, D, G Sarwar, andL Savoiet. “Purine Content of Selected Canadian Food Products.” Journalof Food Composition and Analysis 1, no. 2 (1988): 130-138.). A survey ofthe world literature on nucleic acid content of foods was conducted. Insome cases where the individual nucleotides were not reported, theamount of total nucleotides and of guanosine-containing nucleotidescould be estimated from the reported purine content. A set of diets withdifferent percentages of nucleotides (compared to the typical Westerndiet) was created. These range between about 10% to 40% of the typicalWestern diet. A registered dietitian created these diets which were lowin nucleotides but balanced for other necessary nutrients.

Choosing a diet with a given percent (or range) of nucleotides isoptimized by medical evaluation of the condition and needs of theindividual patient. Medical evaluation may include the following: levelof antibody titers such as those of anti-nuclear antibody, anti-dsDNAantibodies, anti-guanosine antibody, evaluation of the presence anddegree of organ damage in kidneys, lungs, joints, brain, and skin,subjective symptomatology such as pain, headaches, and evaluationcriteria.

Additionally, it is proposed that all patients with pathogenicinfections, and individuals susceptible to developing pathogenicinfections, will benefit from diets in which the nucleotide level is 45%or less than the typical western diet, and in which the guanosine andguanosine-containing nucleotides are less than 45% of the typicalwestern diet.

2. The Diets Initially Recommended by the Physician to the Patient areLow in their Content of Guanine, a Nitrogenous Base, and/or Guanosine, aNucleoside, Compared to the Usual Western Diet.

The patient's response to the diet is evaluated over time and diets withsequentially more nucleotide content and more palatability arerecommended so that the compliance and tolerability and palatability isat such a level that the patient can for years be maintained on areduced nucleotide diet. For instance, if the patient is started by thephysician on a Step 1 diet, it is likely that after a period of weeks ormonths the patient will be advanced to a Step 2 diet which has a greaternucleotide content, reflected in a larger range of foods which can betaken, and is therefore more palatable.

(Nucleotide-free diets are described in: Rudolph, F B, A D Kulkarni, W CFanslow, R P Pizzini, S Kumar, and C T Van Buren. “Role of RNA As aDietary Source of Pyrimidines and Purines in Immune Function.” Nutrition6, no. 1(1990): 45-52; Kulkarni, A D, F B Rudolph, and C T Van Buren.“The Role of Dietary Sources of Nucleotides in Immune Function: AReview.” The Journal of nutrition 124, no. 8 Suppl (1994): 1442S-1446S.:45-52).

The inventor's reduced nucleotide diets are fundamentally different fromnucleotide-free diets. The nucleotide-free diets used in publishedanimal experiments were almost entirely devoid of nucleotides and weresaid to contain a level of only 0.001% (Rudolph, F B, A D Kulkarni, W CFanslow, R P Pizzini, S Kumar, and C T Van Buren. “Role of RNA As aDietary Source of Pyrimidines and Purines in Immune Function.” Nutrition6, no. 1 (1990): 45-52).

The inventor has conducted extensive analysis of the nucleotide contentof human foods from a variety of sources, and evaluated the nutritionalcontent and palatability of potential nucleotide-free diets. Theinventor has concluded that it is not practical for most people to stayon a nucleotide-free diet in a compliant manner for the period of monthsrequired to obtain substantial clinical benefit from this approach. Anucleotide-free diet is unlikely to be sufficiently palatable forextended use and would deter compliance. Also, use of a nucleotide-freediet for months in humans would likely lead to other dietarydeficiencies.

As set forth above, the disclosure provides treatment of a patient witha diet which contains approximately 3% to 50% of the amount by weight ofnucleotides seen in the normal western diet, which contains about 2000mg/day of nucleotides. In exemplary embodiments, the diet of thedisclosure contains a nucleotide content of about 1000 mg/day, of about750 mg/day, of about 500 mg/day, of about 250 mg/day, of about 100mg/day, of about 75 mg/day, of about 50 mg/day, of about 25 mg/day. Inexemplary embodiments, the diet of the disclosure contains a nucleotidecontent compared to the normal Western diet of about 50%, of about 40%,of about 30%, of about 20%, of about 10%, of about 5%, of about 3%. Inexemplary embodiments, the diet of the disclosure contains a nucleotidecontent compared to the normal Western diet of 3-50%, of about 10-40%,of about 20-30%, of about 3-40%, of about 3-30%, of about 10-30%, ofabout 10-20%.

2. Example diets: The nucleotide content of one Example Diet is about28±5% of the typical Western diet. The nucleotide content of anotherExample Diet is about 43±5% of the typical Western diet. 3. The dietprogram is comprised of a period of months, e.g. 6 months, during whicha physician and a dietician evaluate and work to optimize diet treatmentfor each pathogenic infection patient.

a. The physician initially evaluates the severity of the patient'sdisease based on signs and symptoms, laboratory tests, evidence of organdamage, etc., and then recommends a specific diet. The patient isfollowed over the next few months with repeat followup diseaseevaluations and diet adjustments by the physician. The patient may beasked to keep, as individually necessary, logs of symptoms such asheadaches, skin rashes, joint pains, etc. These logs are periodicallyreviewed by the physician.

b. The dietician has an initial meeting with the patient in which thepractical aspects of the diet program are explained in detail. Thisfirst visit includes describing weighing the foods to be included in thediet, characterizing the portion size for each type of food, keeping afood log, advising on the effect of cooking on food nucleotide content,etc. The patient will have one or more followup visits, as well asoccasional other phone, email or other communications with the patientto answer questions and direct the treatment.

c. Depending on the severity of the patient's disease, an initial dietwill be selected. As the patient stabilizes clinically or based onlaboratory testing, the patient will be moved through a series of dietswith increasing nucleotide content but which are still substantiallylower compared to the typical Western diet. It is believed that for eachpatient there is a threshold for reactivity, and that if the diets arebelow that threshold the patient will have successfully minimized signs,symptoms, and progression of the pathogenic infection. The goal of theprogram is then to put the patient on a convenient and palatablemaintenance diet which they can pragmatically follow for a period ofyears.

d. A specialized version of the low-guanosine diet has been constructedwhich meets the needs of pregnant women.

Part B—Methods for Administering Melanin, and/or Increasing the BodyContent of Melanin by Modulation of Metabolic Processes.

Melanin from different sources and in different formulations has beenshown to have some therapeutic activity against some viruses, bacteria,fungi and parasites, but is not used clinically at all as far as theinventor has been able to determine. Additionally, melanin is very hard(Majerus, M. E. N., Melanism, New York: Oxford University Press, 1998)and has been shown to represent a physical barrier to pathogens both onthe skin (Tang, Huaping. Regulation and function of the melanizationreaction in Drosophila. Fly 3 (2009): 105-111) and internally. It isamenable to a wide range of administration methods including topical andparenteral. It is generally considered to be non-toxic itself except topathogens. Melanin has also been produced from genetically modifiedorganisms including fungi and bacteria.

The present disclosure involves the use of one or more methods from eachof Part A and part B. A method from Part A and a method from Part B canbe administered together (e.g. in a single formulation, or singly at thesame time), or sequentially in any order (e.g. A method from part Afollowed by a method from part B, or a method from part B followed by amethod from part A)

Guanosine—depleting chemicals such as mycophenolate are active againstmicrobes in much lesser doses than those currently used for its mainindication that of immunosuppression for transplantation.

The present disclosure has the further advantage that it is unlikelythat the Zika virus or other organisms will be able to develop aresistance to both of the different types of attack represented by PartA and Part B together. Another advantage of the present disclosure isthat any microbes which were to develop resistance would still besusceptible to other available therapies.

Mycophenolate

As used herein, “mycophenolates” refers herein to mycophenolic acid(“MPA”) and its analogs, and their pharmaceutically acceptable salts,derivatives, prodrugs, and metabolites. Exemplary mycophenolates for usein the present disclosure include mycophenolic acid and mycophenylatemofetil. Mycophenolic acid, or6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methyl-hex-4-enoicacid, has the structure

Mycophenolate mofetil is the 2-morpholinoethyl ester of mycophenolicacid, and has the formula:

Analogs of mycophenolic acid that have high IMPDH-inhibiting activityare also useful in the practice of the present disclosure includecompounds with varying substituents in the 2-, 4-, 5-, and 6-positionson the mycophenolate core structure, as well as pharmaceuticallyacceptable salts, derivatives, prodrugs, and metabolites of suchmycophenolate analogs. Such compounds are described for example, in thefollowing U.S. patents incorporated herein by reference: U.S. Pat. No.5,688,529 Mycophenolate mofetil high dose oral suspensions; U.S. Pat.No. 5,633,279 5-Substituted derivatives of mycophenolic acid U.S. Pat.No. 5,554,612 4-Amino-6-substituted mycophenolic acid and derivativesU.S. Pat. No. 5,538,969 4-Amino derivatives of 5-substitutedmycophenolic acid U.S. Pat. No. 5,536,747 6-Substituted mycophenolicacid and derivatives U.S. Pat. No. 5,493,030 5-Substituted derivativesof mycophenolic acid; U.S. Pat. No. 5,444,072 6-Substituted mycophenolicacid and derivatives U.S. Pat. No. 5,441,953 4-Amino derivatives ofmycophenolic acid U.S. Pat. No. 5,380,879 Derivatives of mycophenolicacid U.S. Pat. No. 4,861,776 Heterocyclic aminoalkyl esters ofmycophenolic acid and derivatives thereof; U.S. Pat. No. 4,753,935Morpholinoethylesters of mycophenolic acid; U.S. Pat. No. 4,748,173Heterocyclic aminoalkyl esters of mycophenolic acid and derivativesthereof; U.S. Pat. No. 4,727,069 Heterocyclic aminoalkyl esters ofmycophenolic acid, derivatives thereof

Dose and administration time of mycophenolic acid for antiviral effectsare surprisingly different than the current dose and administration timefor prevention of transplant rejection. It is important to understandthat mycophenolic acid's anti-viral effect is likely to require a smallfraction (about 1-2% or less) of the clinical dose which is approved andcommonly used for prevention of transplant rejection. For instance, Chanet al., 2013, p. 612 indicated that for a virus in which mycophenolicacid demonstrated an EC₅₀ of 0.17 mcg/ml, the usual clinical doses ofmycophenolic acid would result in local concentrations 60-300× greaterthan needed. This is directly comparable for our results. For instance,in one of the Norovirus tests we document here, EC₅₀ of 0.151 mcg/mL wasreported. Even less mycophenolic acid would be needed to treat virusessuch as Influenza A H1N1 and RSV in which we report EC₅₀ <0.10 mcg/ml.Dramatically lower doses may suffice for mycophenolic acid to treat Zikavirus, where a value of EC50 of 0.049 mcg/ml was obtained in one of ourtests. Therefore, it is not only possible to achieve adequate bodylevels of mycophenolic acid to treat these viruses clinically, but alsoa small fraction of the current clinical dose may be more than adequate.To et al, 2016 also presented data on page 1812 supporting theseconclusions.

A second beneficial difference in the administration of the mycophenolicacid for antiviral use compared to its current clinical usage is thefollowing. Mycophenolic acid, when currently used clinically to preventtransplant rejection in an individual patient, typically is given formonths or years at doses of 2000 mg to 3000 mg per day, to blocklymphocyte cell proliferation. In contrast, the highly effective lowdose antiviral treatments of the disclosure may require, for example,just one to two weeks of administration in an individual patient to curehis viral infection.

A third beneficial point is that the combination of low dose and shorttime of administration of mycophenolic acid to achieve the antiviraleffect, is likely to drastically decrease the occurrence of those sideeffects (adverse events) which have typically been reported clinicallywhere it is currently used at very high dose for very long periods oftime. At low dose for short periods of time it is extremely unlikely tohave immunosuppressive effects which could be detrimental to the body'sresistance to other pathogens.

A fourth beneficial point is that the low dose, short time ofadministration usage described above may also serve to reduce theteratogenic potential of this drug, which occurs when it is used at highdose for long periods of time.

A fifth beneficial point regarding dosing and time of administrationrelates to those pathogenic infections which result in development ofautoimmunity causing neurological illness such as Guillain-BarreSyndrome, encephalitis, myelitis, paralysis, confusion, weakness, etc.In those situations, for instance, the low effective antiviral dose canbe titrated up so that an appropriate degree of mild immunosuppressionis achieved simultaneously or shortly after the antiviral effect toblock the autoimmunity from causing neurological illness. (It has beendemonstrated that the immunosuppressive effect of mycophenolic acid onlymphocytes is dose-dependent, with lower doses having less effect(Vethe et al., 2008).)

For example, West Nile infection is well-documented to causeneurological illness. In a mouse model where West Nile infection leadsto neurological illness, administration of appropriate doses ofmycophenolic acid is demonstrated to mitigate the degree and occurrenceof neurological illness.

The following references are incorporated herein in their entirety:Chan, J. F., Chan, K. H., Kao, R. Y., To, K. K., Zheng, B. J., Li, C.P., Li, P. T., Dai, J., Mok, F. K., Chen, H., Hayden, F. G., Yuen, K. Y.(2013). Broad-spectrum antivirals for the emerging Middle Eastrespiratory syndrome coronavirus. J Infect 67: 606-616. To, K. K., Mok,K. Y., Chan, A. S., Cheung, N. N., Wang, P., Lui, Y. M., Chan, J. F.,Chen, H., Chan, K. H., Kao, R. Y., Yuen, K. Y. (2016). Mycophenolicacid, an immunomodulator, has potent and broad-spectrum in vitroantiviral activity against pandemic, seasonal and avian influenzaviruses affecting humans. J Gen Virol 97: 1807-1817. Vethe, N. T.,Bremer, S., Rootwelt, H., Bergan, S. (2008). Pharmacodynamics ofmycophenolic acid in CD4+ cells: a single-dose study of IMPDH and purinenucleotide responses in healthy individuals. Therapeutic drug monitoring30: 647-655.

Effectiveness of Mycophenolic Acid Against Influenza

1. Data supporting the effectiveness of mycophenolic acid in treatingimportant and currently clinically relevant strains of influenza.

To et al. (2016) pointed out that the demonstration by Chan et al.(2013) of effectiveness of mycophenolic acid against the historicalInfluenza A(H1N1) strain A/WSN/1933 in a chemical screening assay, wasinsufficient to determine whether it would be effective against otherstrains of influenza. To et al. (2016) then experimentally showed thatmycophenolic acid is effective against pandemic flu H1/415, which isA/Hong Kong/415742/2009, and is sometimes written as A(H1N1)pdm09. Theyalso showed it to be effective against seasonal influenza A(H3N2) virus,and avian-origin influenza A (H7N9), as well as other influenza A andinfluenza B viruses. These strains which they tested include those whichare currently clinically relevant.

2. The disclosure provides for the use of mycophenolic acid to be activealso against the following respiratory viruses: Influenza A H3N2;Influenza A H5N1 (low path); Influenza B (Victoria); Influenza B(Yamagata); Parainfluenza virus-3; Rhinovirus-14; Influenza A H7N9virus; Influenza A H5N1 (high path).

The following references are incorporated herein by reference in theirentireties: Chan, J. F., Chan, K. H., Kao, R. Y., To, K. K., Zheng, B.J., Li, C. P., Li, P. T., Dai, J., Mok, F. K., Chen, H., Hayden, F. G.,Yuen, K. Y. (2013). Broad-spectrum antivirals for the emerging MiddleEast respiratory syndrome coronavirus. J Infect 67: 606-616. To, K. K.,Mok, K. Y., Chan, A. S., Cheung, N. N., Wang, P., Lui, Y. M., Chan, J.F., Chen, H., Chan, K. H., Kao, R. Y., Yuen, K. Y. (2016). Mycophenolicacid, an immunomodulator, has potent and broad-spectrum in vitroantiviral activity against pandemic, seasonal and avian influenzaviruses affecting humans. J Gen Virol 97: 1807-1817. (First PublishedOnline: 1 Aug. 2016.).

In a Zika Prevention Trial, MPA was pre-incubated with human cells 4hours or 24 hours before Zika virus infection. In the VYR assays, MPAreduced virus to zero in Huh7 cells pre-incubated with drug for 24 hrs.

Minocycline, Doxycycline, and Other Tetracycline Derivatives for ZikaTreatment

The disclosure provides the use of minocycline, doxycycline and othertetracycline derivatives, including for example tetracycline, for theprevention and treatment of infection by pathogenic agents, for exampleviruses, and in a specific embodiment the Zika virus. Minocycline is apreferred compound because it will also cross the blood brain barrier.Without being bound by any theory, it is believed that the primarymechanism is inhibition of viral replication, but other propertiesincluding antioxidant and anti-inflammatory effects on the host cellsare believed to contribute. Several tetracycline derivatives have beendemonstrated to inhibit other viruses, including retroviruses and otherflaviviridae (Chapagain, 2012; Dutta, 2010; Michaelis, 2007; Rothan,2014).

Chapagain, M. (2012). Minocycline Protects Mice against West nile virus(WNV)-associated severe disease 18th SNIP Scientific Conference. Journalof Neuroimmune Pharmacology 7: 5-81. Dutta, K., Anirban, B. (2011) Useof minocycline in viral infections. Indian Journal of Medical Research133: 467. Michaelis, M., Kleinschmidt, M. C., Doerr, H. W., Cinatl, J.(2007). Minocycline inhibits West Nile virus replication and apoptosisin human neuronal cells. J Antimicrob Chemother 60: 981-986. Rothan, H.A., Mohamed, Z., Paydar, M., Rahman, N. A., Yusof, R. (2014). Inhibitoryeffect of doxycycline against dengue virus replication in vitro. ArchVirol 159: 711-718.

L-DOPA, Dopamine, and Precursors in the Melanin Synthesis Pathway forZika Treatment

The disclosure provides that L-dopa, dopamine and precursors in themelanin synthesis pathway prevent and treat infection by Zika virus.L-DOPA is a preferred compound because it can be given orally and willalso cross the blood brain barrier. Without being bound by any theory,the primary mechanism is believed to be inhibition of viral replication,but other properties including are believed to contribute. It has beenproposed that in insects, several compounds in the melanin synthesispathways are important in insect immunity and have anti-microbialeffects (Nappi et al., 2005). L-Dopa has been demonstrated to reduceWest Nile virus proliferation somewhat in cell culture, but the RNAlevels of the virus were not reduced by L-Dopa (Blazquez et al., 2016).Blázquez, A. B., Martin-Acebes, M. A., Saiz, J. C. (2016). Inhibition ofWest Nile Virus Multiplication in Cell Culture by Anti-ParkinsonianDrugs. Front Microbiol 7: 296. Nappi, A. J., Christensen, B. M. (2005).Melanogenesis and associated cytotoxic reactions: applications to insectinnate immunity. Insect Biochem Mol Biol 35: 443-459.

Therapeutic Use of Melanin Overview

The present disclosure is directed to therapeutic uses of melanin,melanin precursors, melanin derivatives, melanin analogs and relatedsubstances. One particular aspect of the disclosure relates to thetreatment or prevention of infections by the administration of activesubstances which cause an increased melanin concentration in thepatient's infected tissues. Such substances include melanin, melaninprecursors, melanin derivatives, melanin analogs, melanin variants,melanin-concentrating hormone (MCH), tyrosinase, tyrosinase gene andcombinations thereof.

In one aspect, the present disclosure a method for treating orpreventing pathogenic infections in a mammal comprising administering toa mammal in need of such treatment an amount effective for treating saidinfections of an agent which causes an increased concentration ofmelanin and related substance in said infections.

In another aspect, the present disclosure provides a method forpreventing pathogenic infections in a mammal comprising administering toa mammal in need of such treatment an amount of an agent effective toprevent said infections of an agent which causes an increasedconcentration of melanin and related substances in said infections.

In yet another aspect the present disclosure provides a pathogenicinfection-healing device selected from a patch, a strip, a dressing or aband comprising an amount of melanin or related substance effective totreat a infections in a mammal.

In yet another aspect the present disclosure provides a pharmaceuticalformulation for treating or preventing pathogenic infections in a mammalcomprising mineral oil and an infection treating effective amount of anagent which causes an increase in the concentration of melanin in saidinfected tissues.

In a further aspect, the present disclosure provides a pharmaceuticalformulation for treating or preventing pathogenic infections in a mammalcomprising another topical antibacterial cream or ointment and ainfection-healing effective amount of an agent which causes an increasedconcentration of melanin and related substances in said infections.

In a still further aspect, the present disclosure provides a method fortreating or preventing pathogenic infections in a mammal comprisingadministering to a mammal in need of such treatment an amount effectiveto treat said infections of a pharmaceutical formulation which causes anincrease in the concentration of melanin in said infected tissueswherein said agent is selected from melanin, melanin precursors, melaninderivatives, melanin analogs, melanin variants, tyrosinase, tyrosinasegene, melanin concentration hormone and mixtures thereof.

In a still further aspect, the present disclosure provides apharmaceutical formulation for treating or preventing pathogenicinfections in a mammal comprising an emollient selected from ammoniumlactate, ichthammol ointment and lanolin and an infection-healingeffective amount of an agent which causes an increased concentration ofmelanin and related substances in said infections.

These and other aspects of the present disclosure will be apparent tothose of ordinary skill in the art in light of the present descriptionand claims.

Melanins

Melanin is a pigment which is found in many cells and organisms(Majerus, M. E. N., Melanism, New York: Oxford University Press 1998).It is resistant to analysis and degradation by chemical and physicalagents (Prota, G., Melanins And Melanogenesis, N.Y.: Academic Press,1992). Therefore the complete structures of many melanins remainunknown, although a few have been identified and even synthesized(Prota, G., Melanins And Melanogenesis, N.Y.: Academic Press, 1992).

Melanin is naturally found in small packets called melanosomes (Prota,G., Melanins And York: Academic Press, 1992), which aremembrane-enclosed vesicles. Melanin is a hard substance (Majerus, M. E.N., Melanism, New York: Oxford University Press, 1998). The presence ofmany small melanosomes strengthens cells. The melanin in cells isseparated by membranes and other cytoplasmic components, Thisarrangement permits flexibility in movement while preserving hardness toresist pressure.

Melanin is normally present in mammalian skin in cells calledmelanocytes (Prota, G., Melanins And Melanogenesis, New York: AcademicPress, 1992). Melanocytes are most numerous in the epidermis and dermisof the skin, but are present in other tissues such as the eye, somenerves, the brain, and some blood cells.In the epidermis there is approximately 1 melanocyte to 36keratinocytes. In the dermis the ratio of melanocytes to fibroblasts ismuch more variable. Melanin is often found in healed skin (Majerus, M.E. N., Melanism, New York: Oxford University Press, 1998).

Mammalian colors are determined chiefly by two types, eumelanins andphaeomelanins. Eumelanins are derived from the precursor tyrosine andare generally insoluble and black or brown in color. Phaeomelanins haveas their precursors tyrosine and cysteine and are generallyalkali-soluble and lighter in color. Allomelanins (“allo” meaning other)are formed from nitrogen-free precursors, primarily catechol and1,8-dihydroxynaphthalene (see The Merck Index, Tenth Edition, page 827,item 5629, Melanins). Quinones are the usual intermediates inallomelanin synthesis. The synthesis of melanins occurs in nature aswell as being produced synthetically. A further group of low molecularweight yellow, red and violet pigments is known as trichochromes. Thetrichochromes are usually classified with the melanins, since they serveas pigments and are derived from the oxidation of tyrosine.

The enzyme, tyrosinase, plays a key role in the synthesis of melanin andits derivatives. In mammals, tyrosinase is a glycosylated enzyme foundin melanocytes. It has been theorized that tyrosinase functions by meansof separate catalytic sites; one site for tyrosinase hydroxylaseactivity, another site for dopa oxidase activity, and a thirdindependent site for dopa as a cofactor. (Hearing, V. J. et al.,Biochem. J., 157: 549 (1976)). Tyrosinase may also play a role incatalyzing the oxidation of 5,6-dihydroxyindole to indole-5,6-quinone.(Korner, A. M. et al., Science 217, 1163 (1982)). In vivo, mammaliantyrosinase undergoes extensive modification. When initially synthesized,tyrosinase has an apparent molecular weight of about 55,000.Glycosylation of the enzyme occurs as it is transferred through theGolgi complex and delivered to the melanocytes. (Imokawa, G. et al., J.Invest. Derm., 85, 165 (1985)). During this modification of tyrosinase,sialic acid and 4 mol of asparagine-linked carbohydrate chains(containing mannose, glucosamine, galactose and are added to each moleof tyrosinase. (Ferrini, V. et al., Int. J. Biochem. 19, 229 (1987)).The glycosylated tyrosinase has an apparent molecular weight of about70,000. (Laskin, J. D. et al., J. Biol. Chem. 261, 16626 (1986)). Theglycosylated tyrosinase is delivered to the melanocytes by coatedvesicles. In the melanocytes, the tyrosinase is membrane bound andaggregates into a high molecular weight form. In vivo, tyrosinase isunder active metabolic control involving an active degradation systemwhich results in a biological half-like of about ten hours. (Jimenez, M.et al., Fed. Proc. Fedn. Am. Socs. Exp. Biol. 45, 1714 (1986)).

The melanins comprise a family of biopolymer pigments. A frequently usedchemical description of melanin is that it is comprised of“heteropolymers of 5-6-dihydroxyindole and5-6-dihydroxyindole-2-carboxylic acid” (Bettinger et al., 2009).Melanins are polymers produced by polymerization of reactiveintermediates. The polymerization mechanisms include, but are notlimited to, autoxidation, enzyme-catalyzed polymerization and freeradical initiated polymerization.

The reactive intermediates are produced chemically, electrochemically,or enzymatically from precursors. Suitable enzymes include, but are notlimited to, peroxidases, catalases, polyphenol oxidases, tyrosinases,tyrosine hydroxylases, and laccases. The precursors that are connectedto the reactive intermediates are hydroxylated aromatic compounds.Suitable hydroxylated aromatic compounds include, but are not limitedto 1) phenols, polyphenols, aminophenols and thiophenols of aromatic orpolycyclicaromatic hydrocarbons, including, but not limited to, phenol,tyrosine, pyrogallol, 3-aminotyrosine, thiophenol and α-naphthol; 2)phenols, polyphenols, aminophenols, and thiophenols of aromaticheterocyclic or heteropoly cyclic hydrocarbons such as, but not limitedto, 2-hydroxypyrrole, 4-hydroxy-1,2-pyrazole, 4-hydroxypyridine,8-hydroxyquinoline, and 4,5-dihydroxybenzothiazole.

The term melanin includes naturally occurring melanin polymers as wellas melanin analogs as defined below. Naturally occurring melaninsinclude eumelanins, phaeomelanins, neuromelanins and allomelanins.

As used here, the term “melanin” refers to melanins, melanin precursors,melanin analogs, melanin variants, melanin derivatives, and melanin-likepigments, unless the context dictates otherwise. The term “melanin-like”also refers to hydrogels with melanin-like pigmentation and quinoidelectrophilicity. This electrophilicity can be exploited for facilecoupling with biomolecules.

As used herein, the term “melanin analog” refers to a melanin in which astructural feature that occurs in naturally-occurring orenzymatically-produced melanins is replaced by a substituent divergentfrom substituents traditionally present in melanin. An example of such asubstituent is a selenium, such as selenocysteine, in place of sulfur.

As used herein, the term “melanin derivative” refers to any derivativeof melanin which is capable of being converted to either melanin or asubstance having melanin activity. An example of a melanin derivative ismelanin attached to a dihydrotrigonelline carrier such as described inBodor, N., Ann. N.Y. Acad. Sci. 507, 289 (1987), which enables themelanin to cross the blood-brain barrier. The term melanin derivativesis also intended to include chemical derivatives of melanin, such as anesterified melanin.

As used herein, the term “melanin variant” refers to various subsets ofmelanin substances that occur as families of related materials. Includedin these subsets, but not limited thereto, are:

(1) Naturally occurring melanins produced by whole cells that vary intheir chemical and physical characteristics;

(2) Enzymatically produced melanins prepared from a variety of precursorsubstrates under diverse reaction conditions;

(3) Melanin analogs in which a structural feature that occurs in (1) or(2) above is replaced by an unusual substituent divergent from thetraditional; and

(4) Melanin derivatives in which a substituent in a melanin produced in(1), (2) or

(3) above is further altered by chemical or enzymatic means.

As used herein, the term “Melanin-like substances” refers toheteropolymers of 5-6-dihydroxyindole and5-6-dihydroxyindole-2-carboxylic acid which have one or more propertiesusually associated with natural melanins, such as UV absorption orsemiconductor behavior.

Melanin Sources

Melanin and Melanin-like compounds can be obtained:

-   -   by extraction and purification from natural sources, e.g.        cephalopods such as cuttlefish (e.g. Sepia) or squid (e.g.        Loligo), bird feathers (e.g. from species with black strains        such as Silkie chickens);    -   by chemical synthesis, whether water or non-water based e.g.        (Deziderio, 2004) (daSilva et al., 2004; Lawrie et al., 2008;        Pezzella et al., 2006);        -   by electrochemical synthesis, e.g. (Meredith et al., 2005);        -   by bioreactors created by utilization of natural or            genetically altered bacteria, fungi, lichens, or viruses            e.g. (della-Cioppa, 1998).

Melanin Manufacturing and Fabrication

Melanin and melanin-like compounds can be manufactured as particles,nanoparticles, dust, beads, or fibers that are woven or non-woven e.g.by methods as described by (Greiner and Wendorff, 2007), sheets e.g.(Meredith et al., 2005), films (daSilva et al., 2004), plates, bricks,chars, spheres, nodules, balls, graphite-like sheets and shards,liquids, gels, or solids (e.g. thermoplastic or thermoset), and bycommon chemical engineering molding and fabrication methods or custommethods. Sheets can range from one molecular layer to severalmillimeters. Fibers can range from nanometers to several millimeters.

The melanin material may be natural or synthetic, with natural pigmentsbeing extracted from plant and animal sources, such as squid, octopus,mushrooms, cuttlefish, and the like. In some cases, it may be desirableto genetically modify or enhance the plant or animal melanin source toincrease the melanin production. Melanins are also availablecommercially from suppliers.

The following procedure describes an exemplary technique for theextraction of melanin from cuttlefish (Sepia Officinalis). 100 gm ofcrude melanin are dissected from the ink sac of 10 cuttlefish and washedwith distilled water (3×100 ml). The melanin is collected after eachwash by centrifugation (200×g for 30 minutes). The melanin granules arethen stirred in 800 ml of 8 M Urea for 24 hours to disassemble themelanosomes. The melanin suspension is spun down at 22,000×g for 100minutes and then washed with distilled water (5×400 ml). The pellet iswashed with 50% aqueous DMF (5×400 ml) until a constant UV baseline isachieved from the washes. Finally, the pellet is washed with acetone(3×400 ml) and allowed to air dry.

Synthetic melanins may be produced by enzymatic conversion of suitablestarting materials, as described in more detail hereinbelow. Themelanins may be formed in situ within the porous particles or may bepreformed with subsequent absorption into the porous particles.

Suitable melanin precursors include but are not limited to tyrosine,3,4-dihydroxy phenylalanine (dopa), D-dopa, catechol, 5-hydroxyindole,tyramine, dopamine, m-aminophenol, o-aminophenol, p-aminophenol,4-aminocatechol, 2-hydroxyl-1,4-naphthaquinone (henna), 4-methylcatechol, 3,4-dihydroxybenzylamine, 3,4-dihydroxybenzoic acid,1,2-dihydroxynaphthalene, gallic acid, resorcinol, 2-chloroaniline,p-chloroanisole, 2-amino-p-cresol, 4,5-dihydroxynaphthalene2,7-disulfonic acid, o-cresol, m-cresol, p-cresol, and other relatedsubstances which are capable of being oxidized to tan, brown, or blackmelanin-like compounds capable of absorbing ultraviolet radiation whenincorporated in the polymeric particle matrix of the present disclosure.Combinations of precursors can also be used.

The melanin precursor is dissolved in an aqueous solution, typically atan elevated temperature to achieve complete solution. A suitable amountof the enzyme tyrosinase (EC 1.14.18.1) is added to the solution, eitherbefore or after the melanin precursor. The concentration of tyrosinaseis not critical, typically being present in the range from about 50 toabout 5000 U/ml. The solution is buffered with an acetate, phosphate, orother suitable buffer, to a pH in the range from about 3 to 10, usuallyin the range from about 5 to 8, more usually being about 7. Melanin-likepigments can be obtained using suitable precursors even in the absenceof an enzyme just by bubbling oxygen through a solution of a precursorfor an adequate period of time.

Melanin material may be obtained by treatment of, e.g, cuttlefish ink orsquid ink in a microwave, optionally with mixing.

Topical Administration of Melanin

Presented below are non limiting categories of topical agents andspecific examples of commercially available products into which melaninand related substance may be incorporated. Burn Treatments SilverSulfadiazine Cream 1% (catalog number. 32886 Henry Schein, Inc.)Emollients Ammonium Lactate Cream (catalog number. 1027036, HenrySchein, Inc.) Ichthammol Ointment-20% (catalog number 1020956, HenrySchein, Inc.) Lanolin (catalog number 1021756, Henry Schein, Inc.

Sun Screen Products Zinc Oxide and ointment (catalog number 4711456,Henry Schein, Inc.) Antibiotics and Antibacterials Bacitracin Ointment(catalog number 4706972, Henry Schein, Inc.) Clindamycin Topicalsolution (catalog number 1028791, Henry Schein, Inc.) Cream (catalognumber 1027125, Henry Schein, Inc.) Erythromycin topical solution(catalog number 4207358, Henry Schein, Inc.) Gentamycin ointment(catalog number 4733872, Henry Schein, Inc.) Nystatin cream (catalognumber 4201056, Henry Schein, Inc.) and Antiseborreics ClotrimazoleBetamethasone cream (catalog number 1025190, Henry Schein, Inc.)Ketoconoizole Cream (catalog number 1024347, Henry Schein, Inc.)Miconiazole Nitrate Cream (catalog number 2723761, Henry Schein, Inc.)Nystatin Ointment (catalog number 1020986, Henry Schein, Inc.)Antiseptics Alcohol, Isopropyl 91% (catalog number Henry Schein, Inc.)Hydrogen Peroxide (catalog number 1023516, Henry Schein, Inc.) Isopropylalcohol 70% (catalog number 1024716, Henry Schein, Inc.) PovidoneOintment (catalog number 4722656, Henry Schein, Inc.)

Viruses

A non-exhaustive list of viruses and their species which can beprevented and/or treated by the compostions and methods of thedisclosure include, for example: Abadina virus (Reoviridae), Abelsonmurine leukemia virus (Retroviridae), Abras virus (Bunyaviridae),Absettarov virus (Flaviviridae), Abu Hammad virus (Bunyaviridae), AbuMina virus (Bunyaviridae), Acado virus (Reoviridae), Acara virus(Bunyaviridae), Acciptrid herpesvirus (Herpesviridae), Acheta domesticadensovirus (Parvoviridae), Acrobasis zelleri entomopoxvirus(Poxviridae), Adelaide River virus (Rhabdoviridae), Adeno-associatedvirus (Parvoviridae), Aedes aegypti densovirus (Parvoviridae), Aedesaegypti entomopoxvirus (Poxviridae), Aedes albopictus densovirus(Parvoviridae), Aedes pseudoscutellaris densovirus (Parvoviridae),African green monkey cytomegalovirus (Herpesviridae), African greenmonkey HHV-like virus (Herpesviridae), African green monkey polyomavirus(Papovaviridae), African horse sickness viruses (Reoviridae), Africanswine fever virus, African swine fever-like viruses, AG-virus(Bunyaviridae), AG-virus, (Bunyaviridae), Agaricus bisporus virus,Aguacate virus (Bunyaviridae), Ahlum water-borne virus (Tombusviridae),Aino virus (Bunyaviridae), Akabane virus (Bunyaviridae), AKR(endogenous) murine leukemia virus (Retroviridae), Alajuela virus(Bunyaviridae), Alcelaphine herpesvirus (Herpesviridae), Alenquer virus(Bunyaviridae), Aleutian disease virus (Parvoviridae), Aleutian minkdisease virus (Parvoviridae), Alfuy virus (Flaviviridae), Allerton virus(Herpesviridae), Allitrich herpesvirus (Herpesviridae), Allomycesarbuscula virus, Almeirim virus (Reoviridae), Almpiwar virus(Rhabdoviridae), Altamira virus, (Reoviridae), Amapari virus(Arenaviridae), American ground squirrel herpesvirus, (Herpesviridae),Amsacta moorei entomopoxvirus (Poxviridae), Amyelosis chronic stuntvirus (Caliciviridae), Ananindeua virus (Bunyaviridae), Anatidherpesvirus (Herpesviridae), Andasibe virus (Reoviridae), Anhanga virus(Bunyaviridae), Anhembi virus (Bunyaviridae), Anomala cupreaentomopoxvirus (Poxviridae), Anopheles A virus (Bunyaviridae), Anophelesvirus (Bunyaviridae), Antequera virus (Bunyaviridae), Aotine herpesvirus(Herpesviridae), Apeu virus (Bunyaviridae), Aphodius tasmaniaeentomopoxvirus (Poxviridae), Apoi virus (Flaviviridae), Aransas Bayvirus (Bunyaviridae), Arbia virus (Bunyaviridae), Arboledas virus(Bunyaviridae), Arbroath virus (Reoviridae), Argentine turtleherpesvirus (Herpesviridae), Arkonam virus (Reoviridae), Aroa virus(Flaviviridae), Arphia conspersa entomopoxvirus (Poxviridae), Aruacvirus (Rhabdoviridae), Arumowot virus (Bunyaviridae), Asinineherpesvirus (Herpesviridae), Atlantic cod ulcus syndrome virus(Rhabodoviridae), Atlantic salmon reovirus Australia (Reoviridae),Atlantic salmon reovirus Canada (Reoviridae), Atlantic salmon reovirusUSA (Reoviridae), Atropa belladorma virus (Rhabdoviridae), Aucubabacilliform virus, Badnavirus, Aujeszky's disease virus (Herpesviridae),Aura virus (Togaviridae), Auzduk disease virus (Poxviridae), Avalonvirus (Bunyaviridae), Avian adeno-associated virus (Parvoviridae), Aviancarcinoma, Mill Hill virus (Retroviridae), Avian encephalomyelitis virus(Picornaviridae), Avian infectious bronchitis virus (Coronaviridae),Avian leukosis virus-RSA (Retroviridae), Avian myeloblastosis virus(Retroviridae), Avian myelocytomatosis virus (Retroviridae), Aviannephrites virus (Picornaviridae), Avian paramyxovirus (Paramyxoviridae),Avian reovirus (Reoviridae), B virus (Parvoviridae), B-lymphotropicpapovavirus (Papovaviridae), Babahoya virus (Bunyaviridae), Babankivirus (Togaviridae), Baboon herpesvirus (Herpesviridae), Baboonpolyomavirus (Papovaviridae), Bagaza virus (Flaviviridae), Bahia Grandevirus (Rhabdoviridae), Bahig virus (Bunyaviridae), Bakau virus(Bunyaviridae), Baku virus (Reoviridae), Bald eagle herpesvirus(Herpesviridae), Bandia virus (Bunyaviridae), Bangoran virus(Rhabdoviridae), Bangui virus (Bunyaviridae), Banzi virus(Flaviviridae), Barmah Forest virus (Togaviridae), Barranqueras virus(Bunyaviridae), Barur virus (Rhabdoviridae), Batai virus (Bunyaviridae),Batarna virus (Bunyaviridae), Batken virus (Bunyaviridae), Bauline virus(Reoviridae), Beak and feather disease virus (Circoviridae), BeAn virus(Rhabdoviridae), BeAr virus (Bunyaviridae), Bebaru virus (Togaviridae),Belem virus (Bunyaviridae), Belmont virus ((Bunyaviridae)), Belterravirus (Bunyaviridae), Benevides virus (Bunyaviridae), Benfica virus(Bunyaviridae), Berne virus, (Coronaviridae), Berrimah virus(Rhabdoviridae), Bertioga virus (Bunyaviridae), Bhanja virus(Bunyaviridae), Bimbo virus (Rhabdoviridae), Bimiti virus(Bunyaviridae), Birao virus (Bunyaviridae), BivensArm virus(Rhabdoviridae), BK virus (Papovaviridae), Bluetongue viruses(Reoviridae), Bobaya virus (Bunyaviridae), Bobia virus (Bunyaviridae),Bobwhite quail herpesvirus (Herpesviridae), Boid herpesvirus(Herpesviridae), Bombyx mori densovirus (Parvoviridae), Boolarra virus(Nodaviridae), Boraceia virus (Bunyaviridae), Border disease virus(Flaviviridae), Boma disease virus, Botambi virus (Bunyaviridae), Botekevirus, (Rhabdoviridae), Bouboui virus (Flaviviridae), Bovineadeno-associated virus (Parvoviridae), Bovine adenoviruses(Adenoviridae), Bovine astrovirus (Astroviridae), Bovine coronavirus(Coronaviridae), Bovine diarrhea virus (Flaviviridae), Bovineencephalitis herpesvirus (Herpesviridae), Bovine enteric calicivirus(Caliciviridae), Bovine enterovirus (Picornaviridae), Bovine ephemeralfever virus (Rhabdoviridae), Bovine herpesvirus (Herpesviridae), Bovineimmunodeficiency virus (Retroviridae), Bovine leukemia virus(Retroviridae), Bovine mamillitis virus (Herpesviridae), Bovinepapillomavirus (Papovaviridae), Bovine papular stomatitis virus(Poxviridae), Bovine parainfluenza virus (Paramyxoviridae), Bovineparvovirus (Parvoviridae), Bovine polyomavirus (Papovaviridae), BovineRespiratory Syncytial Virus (Paramyxoviridae), Bovine rhinovirus(Picornaviridae), Bovine syncytial virus (Retroviridae), Bozo virus(Bunyaviridae), Broadhaven virus (Reoviridae), Bruconha virus(Bunyaviridae), Brus Laguna virus (Bunyaviridae), Budgerigar fledglingdisease virus (Papovaviridae), Buenaventura virus (Bunyaviridae),Buffalopox virus (Poxviridae), Buggy Creek virus (Togaviridae), Bujaruvirus (Bunyaviridae), Bukalasa bat virus (Flaviviridae), Bunyamweravirus (Bunyaviridae), Bunyip creek virus (Reoviridae), Bushbush virus(Bunyaviridae), Bussuquara virus (Flaviviridae), Bwamba virus(Bunyaviridae), Cache Valley virus (Bunyaviridae), Cacipacore virus(Flaviviridae), Caddo Canyon virus (Bunyaviridae), Caimito virus(Bunyaviridae), Calchaqui virus (Rhabdoviridae), California encephalitisvirus (Bunyaviridae), California harbor sealpox virus (Poxviridae),Callistephus chinensis chlorosis virus (Rhabdoviridae), Callitrichineherpesvirus (Herpesviridae), Camel contagious ecthyma virus(Poxviridae), Camelpox virus (Poxviridae), Camptochironomus tentansentomopoxvirus (Poxviridae), Cananeia virus (Bunyaviridae), Canarypoxvirus (Poxviridae), Candiru virus (Bunyaviridae), Canid herpesvirus(Herpesviridae), Caninde virus (Reoviridae), Canine adeno-associatedvirus (Parvoviridae), Canine adenovirus (Adenoviridae), Caninecalicivirus (Caliciviridae), Canine coronavirus (Coronaviridae), Caninedistemper virus (Paramyxoviridae), Canine herpesvirus (Herpesviridae),Canine minute virus (Parvoviridae), Canine oral papillomavirus(Papovaviridae), Canine parvovirus (Parvoviridae), Canna yellow mottlevirus (Badnavirus), Cape Wrath virus (Reoviridae), Capim virus(Bunyaviridae), Caprine adenovirus (Adenoviridae), Caprine arthritisencephalitis virus (Retroviridae), Caprine herpesvirus (Herpesviridae),Capuchin herpesvirus AL- (Herpesviridae), Capuchin herpesvirus AP-(Herpesviridae), Carajas virus (Rhabdoviridae), Caraparu virus(Bunyaviridae), Carey Island virus (Flaviviridae), Casphalia extraneadensovirus (Parvoviridae), Catu virus (Bunyaviridae), Caviid herpesvirus((Herpesviridae)), CbaAr virus (Bunyaviridae), Cebine herpesvirus(Herpesviridae), Cercopithecine herpesvirus (Herpesviridae), Cervidherpesvirus (Herpesviridae), CG-virus (Bunyaviridae), Chaco virus(Rhabdoviridae), Chagres virus (Bunyaviridae), Chamois contagiousecthyma virus (Poxviridae), Chandipura virus (Rhabdoviridae),Changuinola virus (Reoviridae), Charleville virus (Rhabdoviridae),Chelonid herpesvirus (Herpesviridae), Chelonid herpesvirus(Herpesvirzdae), Chelonid herpesvirus (Herpesviridae), Chenuda virus(Reoviridae), Chick syncytial virus (Retroviridae), Chicken anemia virus(Circoviridae), Chicken parvovirus (Paruoviridae), Chikungunya virus(Togaviridae), Chilibre virus (Bunyaviridae), Chim virus (Bunyaviridae),Chimpanzee herpesvirus (Herpesviridae), Chironomus attenuatusentomopoxvirus (Poxviridae), Chironomus luridus entomopoxvirus(Poxviridae), Chironomus plumosus erltomopoxvirus (Poxviridae), ChobarGorge virus (Reoviridae), Choristoneura biennis entomopoxvirus(Poxviridae), Choristoneura conflicta entomopoxvirus (Poxviridae),Choristoneura diversuma entomopoxvirus (Poxviridae), Chorizagrotisauxiliars entomopoxvirus (Poxviridae), Chub reovirus Germany(Reoviridae), Ciconiid herpesvirus (Herpesviridae), Clo Mor virus(Bunyaviridae), CoAr-virus (Bunyaviridae), Coastal Plains virus(Rhabdoviridae), Cocal virus (Rhabdoviridae), Coital exanthema virus(Herpesviridae), ColAn-virus (Bunyaviridae), Colocasia bobone diseasevirus, (Rhabdoviridae), Colorado tick fever virus, (Reoviridae),Columbia SK virus, (Picornaviridae), Columbid herpesvirus,(Herpesviridae), Connecticut virus, (Rhabdoviridae), Contagious ecthymavirus, (Poxviridae), Contagious pustular dermatitis virus, (Poxviridae),Corfu virus, (Bunyaviridae), Corriparta virus, (Reoviridae), Cotiavirus, (Poxviridae), Cowpox virus, (Poxviridae), Crimean-Congohemorrhagic fever virus, (Bunyaviridae), CSIRO village virus,(Reoviridae), Cynara virus, (Rhabdoviridae), Cyprinid herpesvirus,(Herpesviridae), Dabakala virus, (Bunyaviridae), D'Aguilar virus,(Reoviridae), Dakar bat virus, (Flaviviridae), DakArk virus,(Rhabdoviridae), Deer papillomavirus, (Papovaviridae), Demodemaboranensis entomopoxvirus, (Poxviridae), Dengue virus, (Flaviviridae),Dengue virus group, (Flaviviridae), Dependovirus, (Parvoviridae), DeraGhazi Khan virus, (Bunyaviridae), Dera Ghazi Khan virus Group,(Bunyaviridae), Dermolepida albohirtum entomopoxvirus, (Poxviridae),Dhori virus, (Orthomyxoviridae), Diatraea saccharalis densovirus,(Parvoviridae), Dobrava-Belgrade virus, (Bunyaviridae), Dolphindistemper virus, (Paramyxoviridae), Dolphinpox virus, (Poxviridae),Douglas virus, (Bunyaviridae), Drosophila C virus, (Picornaviridae), DryTortugas virus, (Bunyaviridae), duck adenovirus, (Adenoviridae), Duckadenovirus, (Adenoviridae), Duck astrovirus, (Astroviridae), Duckhepatitis B virus, (Hepadnaviridae), Duck plague herpesvirus syn. anatidherpesvirus, (Herpesviridae), Dugbe virus, (Bunyaviridae), Duvenhagevirus, (Rhabdoviridae), Eastern equine encephalitis virus,(Togaviridae), Ebola virus Filoviridae, Echinochloa hoja blanca virus;Genus Tenuivirus, Echinochloa ragged stunt virus, (Reoviridae),ectromelia virus, (Poxviridae), Edge Hill virus, (Flaviviridae), Egtvedvirus syn. viral hemorrhagic septicemia virus, (Rhabdoviridae), Elapidherpesvirus, (Herpesviridae), Elephant loxondontal herpesvirus,(Herpesviridae), Elephant papillomavirus, (Papovaviridae), Elephantidherpesvirus, (Herpesviridae), Ellidaey virus, (Reoviridae), Embu virus,(Poxviridae), Encephalomyocarditis virus, (Picornaviridae), Enseadavirus, (Bunyaviridae), Entamoeba virus, (Rhabdoviridae), Entebbe batvirus, (Flaviviridae), Epizootic hemorrhagic disease viruses,(Reoviridae), Epstein-Barr virus, (Herpesviridae), Equid herpesvirus,(Herpesviridae), Equid herpesvirus, (Nerpesviridae), Equid herpesvirus,(Herpesviridae), Equine abortion herpesvirus, (Herpesviridae), Equineadeno-associated virus, (Parvoviridae), Equine adenovirus,(Adenoviridae), Equine arteritis virus, (Arterivirus), Equinecytomegalovirus, (Herpesviridae), Equine encephalosis viruses,(Reoviridae), Equine herpesvirus, (Herpesviridae), Equine infectiousanemia virus, (Retroviridae), Equine papillomavirus, (Papovaviridae),Equine rhinopneumonitis virus, (Herpesviridae), Equine rhinovirus,(Picornaviridae), Eret-virus, (Bunyaviridae), Erinaceid herpesvirus,(Herpesviridae), Erve virus, (Bunyaviridae), Erysimum latent virus,Tymovirus, Esocid herpesvirus, (Herpesviridae), Essaouira virus,(Reoviridae), Estero Real virus, (Bunyaviridae), Eubenangee virus,(Reoviridae), Euonymus fasciation virus, (Rhabdoviridae), European batvirus, (Rhabdoviridae), European brown hare syndrome virus,(Caliciviridae), European elk papillomavirus, (Papovaviridae), Europeanground squirrel cytomegalovirus, (Herpesviridae), European hedgehogherpesvirus, (Herpesviridae), Everglades virus, (Togaviridae), Eyachvirus, (Reoviridae), Facey's Paddock virus, (Bunyaviridae), Falconinclusion body disease, (Herpesviridae), Falconid herpesvirus,(Herpesviridae), Farallon virus, (Bunyaviridae), Felid herpesvirus,(Herpesviridae), Feline calicivirus, (Caliciviridae), Felineherpesvirus, (Herpesviridae), Feline immunodeficiency virus,(Retroviridae), Feline infectious peritonitis virus, (Coronaviridae),Feline leukemia virus, (Retroviridae), Feline parlleukopenia virus,(Parvoviridae), Feline parvovirus, (Parvoviridae), Feline syncytialvirus, (Retroviridae), Feline viral rhinotracheitis virus,(Herpesviridae), Fetal rhesus kidney virus, (Papovaviridae), Field mouseherpesvirus, (Herpesviridae), Figulus subleavis entomopoxvirus,(Poxviridae), Fiji disease virus, (Reoviridae), Fin V-virus,(Bunyaviridae), Finkel-Biskis-Jinkins murine sarcoma virus,(Retroviridae), Flanders virus, (Rhabdoviridae), Flexal virus,(Arenaviridae), Flock house virus, Nodaviridae, Foot-and-mouth diseasevirus A, (Picornaviridae), Foot-and-mouth disease virus ASIA,(Picornaviridae), Foot-and-mouth disease virus, (Picornaviridae),Forecariah virus, (Bunyaviridae), Fort Morgan virus, (Togaviridae), FortSherman virus, (Bunyaviridae), Foula virus, (Reoviridae), Fowladenoviruses, (Adenoviridae), Fowl calicivirus, (Caliciviridae), Fowlpoxvirus, (Poxviridae), Fraser Point virus, (Bunyaviridae), Friend murineleukemia virus, (Retroviridae), Frijoles virus, (Bunyaviridae), Frogherpesvirus, (Herpesviridae), Fromede virus, (Reoviridae), Fujinamisarcoma virus, (Retroviridae), Fukuoka virus, (Rhabdoviridae), GabekForest virus, (Bunyaviridae), Gadget's Gully virus, (Flaviviridae),Galleria mellonella densovirus, (Parvoviridae), Gallid herpesvirus,(Herpesviridae), Gamboa virus, (Bunyaviridae), Gan Gan virus,(Bunyaviridae), Garba virus, (Rhabdoviridae), Gardner-Arnstein felinesarcoma virus, (Retroviridae), Geochelone carbonaria herpesvirus,(Herpesviridae), Geochelone chilensis herpesvirus, (Herpesviridae),Geotrupes sylvaticus entomopoxvirus, (Poxviridae), Gerbera symptomlessvirus, (Rhabdoviridae), Germiston virus, (Bunyaviridae), Getah virus,(Togaviridae), Gibbon ape leukemia virus, (Retroviridae), Gingerchlorotic fleckvirus, Sobemovirus, Glycine mottle virus, Tombusviridae,Goat herpesvirus, (Herpesviridae), Goatpox virus, (Poxviridae),Goeldichironomus holoprasimus entomopoxvirus, (Poxviridae), Goldenshiner reovirus, (Reoviridae), Gomoka virus, (Reoviridae), Gomphrenavirus, (Rhabdoviridae), Gonometa virus, (Picornaviridae), Gooseadenoviruses, (Adenoviridae), Goose parvovirus, (Parvoviridae), Gordilvirus, (Bunyaviridae), Gorilla herpesvirus, (Herpesviridae), Gossasvirus, (Rhabdoviridae), Grand Arbaud virus, (Bunyaviridae), Gray Lodgevirus, (Rhabdoviridae), Gray patch disease agent of green sea turtle,(Herpesviridae), Great Island virus, (Reoviridae), Great Saltee Islandvirus, (Reoviridae), Great Saltee virus, (Bunyaviridae), Green iguanaherpesvirus, (Herpesviridae), Green lizard herpesvirus, (Herpesviridae),Grey kangaroopox virus, (Poxviridae), Grimsey virus, (Reoviridae),Ground squirrel hepatitis B virus, (Hepadnaviridae), GroupA-Krotaviruses, (Reoviridae), Gruid herpesvirus, (Herpesviridae),GUU-virus, (Bunyaviridae), Guajara virus, (Bunyaviridae), Guama virus,(Bunyaviridae), Guanarito virus, (Arenaviridae), Guaratuba virus,(Bunyaviridae), Guaroa virus, (Bunyaviridae), Guinea pigcytomegalovirus, (Herpesviridae), Guinea pig herpesvirus,(Herpesviridae), Guinea pig type C oncovirus, (Retroviridae), GumboLimbo virus, (Bunyaviridae), Gurupi virus, (Reoviridae), H-virus,(Parvoviridae), H virus, (Bunyaviridae), Hamster herpesvirus,(Herpesviridae), Hamster polyomavirus, (Papovaviridae), Hantaan virus,(Bunyaviridae), Hanzalova virus, (Flaviviridae), Hardy-Zuckerman felinesarcoma virus, (Retroviridae), Hare fibroma virus, (Poxviridae), HartPark virus, (Rhabdoviridae), Hartebeest herpesvirus, (Herpesviridae),Harvey murine sarcoma virus, (Retroviridae), Hazara virus,(Bunyaviridae), HB virus, (Parvoviridae), Hepatitis virus,(Picornaviridae), Hepatitis virus, (Hepadnaviridae), Hepatitis virus,(Flaviviridae), Herpesvirus M, (Herpesviridae), Herpesvirus papio,(Herpesviridae), Herpesvirus platyrrhinae type, (Herpesviridae),Herpesvirus pottos, (Herpesviridae), Herpesvirus saimiri,(Herpesviridae), Herpesvirus salmonis, (Herpesviridae), Herpesvirussanguinus, (Herpesviridae), Herpesvirus scophthalmus, (Herpesviridae),Herpesvirus sylvilagus, (Herpesviridae), Herpesvirus T, (Herpesviridae),Herpesvirus tarnarinus, (Herpesviridae), Highlands J virus,(Togaviridae), Hirame rhabdovirus, (Rhabdoviridae), Hog cholera virus,(Flaviviridae), HoJo virus, (Bunyaviridae), Hepatitis delta virus,Satellites, Deltavirus, Hsiung Kaplow herpesvirus, (Herpesviridae),Hepatitis E virus, (Caliciviridae), Hepatopancreatic parvo-like virus ofshrimps, (Parvoviridae), Heron hepatitis B virus, (Hepadnaviridae),Herpes ateles, (Herpesviridae), Herpes simiae virus, (Herpesviridae),Herpes simplex virus, (Herpesviridae), Herpes virus B, (Herpesviridae),Herpesvirus aotus, (Herpesviridae), Herpesvirus ateles strain,(Herpesviridae), Herpesvirus cuniculi, (Herpesviridae), Herpesviruscyclopsis, (Herpesviridae), Huacho virus, (Reoviridae), Hughes virus,(Bunyaviridae), Human adenoviruses, (Adenoviridae), Human astrovirus,(Astroviridae), Human calicivirus, (Caliciviridae), Human caliciviruses,(Caliciviridae), Human coronavirus E, (Coronaviridae), Human coronavirusOC, (Coronaviridae), Human coxsackievirus, (Picornaviridae), Humancytomegalovirus, (Herpesviridae), Human echovirus, (Picornaviridae),Human enterovirus, (Picornaviridae), Human foamy virus, (Retroviridae),Human herpesvirus, (Herpesviridae), Human herpesvirus, Nerpesviridae,Human herpesvirus, (Herpesviridae), Human immunodeficiency virus,(Retroviridae), Human papillomavirus, (Papovaviridae), Humanparainfluenza virus, (Paramyxoviridae), Human poliovirus,(Picornaviridae), Human Respiratory Syncytial Virus, (Paramyxoviridae),Human rhinovirus, (Picornaviridae), Human spumavirus, (Retroviridae),Human T-lymphotropic virus, (Retroviridae), Humpty Doo virus,(Rhabdoviridae), HV-virus, (Bunyaviridae), Hypr virus, (Flaviviridae),Laco virus, (Bunyaviridae), Ibaraki virus, (Reoviridae), Icoaraci virus,(Bunyaviridae), Ictalurid herpesvirus, (Herpesviridae), Len virus,(Reoviridae), Ife virus, (Reoviridae), Iguanid herpesvirus,(Herpesviridae), Ilesha virus, (Bunyaviridae), Ilheus virus,(Flaviviridae), Inclusion body rhinitis virus, (Herpesviridae),Infectious bovine rhinotracheitis virus, (Herpesviridae), Infectiousbursal disease virus, Birnaviridae, Infectious hematopoietic necrosisvirus, (Rhabdoviridae), Infectious laryngotracheitis virus,(Herpesviridae), Infectious pancreatic necrosis virus, Birnavirzdae,InfluenzaA virus (A/PR//(HN), (Orthomyxoviridae), Influenza B virus(B/Lee/), (Orthomyxoviridae), Influenza C virus (C/California/),(Orthomyxoviridae), Ingwavuma virus, (Bunyaviridae), Inini virus,(Bunyaviridae), Inkoo virus, (Bunyaviridae), Inner Frame virus,(Reoviridae), Ippy virus, (Arenaviridae), Irituia virus, (Reoviridae),Isfahan virus, (Rhabdoviridae), Israel turkey meningoencephalitis virus,(Flaviviridae), Issyk-Kul virus, (Bunyaviridae), Itaituba virus,(Bunyaviridae), Itaporanga virus, (Bunyaviridae), Itaqui virus,(Bunyaviridae), Itimirirn virus, (Bunyaviridae), Itupiranga virus,(Reoviridae), Jaagsiekte virus, (Retroviridae), Jacareacanga virus,(Reoviridae), Jamanxi virus, (Reoviridae), Jamestown Canyon virus,(Bunyaviridae), Japanaut virus, (Reoviridae), Japanese encephalitisvirus, (Flaviviridae), Jan virus, (Reoviridae), JC virus,(Papovaviridae), Joa virus, (Bunyaviridae), Joinjakaka virus,(Rhabdoviridae), Juan Diaz virus, (Bunyaviridae), Jugra virus,(Flaviviridae), Juncopox virus, (Poxviridae), Junin virus,(Arenaviridae), Junonia coenia densovirus, (Parvoviridae), Jurona virus,(Rhabdoviridae), Jutiapa virus, (Flaviviridae), K virus,(Papovaviridae), K virus, (Bunyaviridae), Kachemak Bay virus,(Bunyaviridae), Kadarn virus, (Flaviviridae), Kaeng Khoi virus,(Bunyaviridae), Kaikalur virus, (Bunyaviridae), Kairi virus,(Bunyaviridae), Kaisodi virus, (Bunyaviridae), Kala Iris virus,(Reoviridae), Kamese virus, (Rhabdoviridae), Karnmavanpettai virus,(Reoviridae), Kannamangalam virus, (Rhabdoviridae), Kao Shuan virus,(Bunyaviridae), Karimabad virus, (Bunyaviridae), Karshi virus,(Flaviviridae), Kasba virus, (Reoviridae), Kasokero virus,(Bunyaviridae), Kedougou virus, (Flaviviridae), Kemerovo virus,(Reoviridae), Kenai virus, (Reoviridae), Kennedya virus Y, Potyviridae,Kern Canyon virus, (Rhabdoviridae), Ketapang virus, (Bunyaviridae),Keterah virus, (Bunyaviridae), Keuraliba virus, (Rhabdoviridae),Keystone virus, (Bunyaviridae), Kharagysh virus, (Reoviridae), Khasanvirus, (Bunyaviridae), Kilham rat virus, (Parvoviridae), Kimberleyvirus, (Rhabdoviridae), Kindia virus, (Reoviridae), Kinkajouherpesvirus, (Herpesviridae), Kirsten murine sarcoma virus,(Retroviridae), Kismayo virus, (Bunyaviridae), Klamath virus,(Rhabdoviridae), Kokobera virus, (Flaviviridae), Kolongo virus,(Rhabdoviridae), Koolpinyah virus, (Rhabdoviridae), Koongol virus,(Bunyaviridae), Kotonkan virus, (Rhabdoviridae), Koutango virus,(Flaviviridae), Kowanyama virus, (Bunyaviridae), Kumlinge virus,(Flaviviridae), Kunjin virus, (Flaviviridae), Kwatta virus,(Rhabdoviridae), Kyzylagach virus, (Togaviridae), La Crosse virus,(Bunyaviridae), La Joya virus, (Rhabdoviridae),La-Piedad-Michoacan-Mexico virus, (Paramyxoviridae), Lacertidherpesvirus, (Herpesviridae), Lactate dehydrogenase-elevating virus,(Arterivirus), Lagos bat virus, (Rhabdoviridae), Lake Clarendon virus,(Reoviridae), Lake Victoria cormorant herpesvirus, (Herpesviridae),Langat virus, Flaviviridae, Langur virus, (Retroviridae), Lanjan virus,(Bunyaviridae), Lapine parvovirus, (Parvoviridae), Las Maloyas virus,(Bunyaviridae), Lassa virus, (Arenaviridae), Lato river virus,(Tombusviridae), Le Dantec virus, (Rhabdoviridae), Leanyer virus,(Bunyaviridae), Lebombo virus, (Reoviridae), Lednice virus,(Bunyaviridae), Lee virus, (Bunyaviridae), Leporid herpesvirus,(Herpesviridae), Leucorrhinia dubia densovirus, (Parvoviridae), Lipovnikvirus, (Reoviridae), Liverpool vervet monkey virus, (Herpesviridae),Llano Seco virus, (Reoviridae), Locusta migratona entomopoxvirus,(Poxviridae), Lokem virus, (Bunyaviridae), Lone Star virus,(Bunyaviridae), Lorisine herpesvirus, (Herpesviridae), Louping illvirus, Flaviviridae, Lucke frog herpesvirus, (Herpesviridae), Lum virus,(Parvoviridae), Lukuni virus, (Bunyaviridae), Lumpy skin disease virus,(Poxviridae), Lundy virus, (Reoviridae), Lymantria dubia densovirus,(Parvoviridae), Lymphocytic choriomeningitis virus, (Arenaviridae),Machupo virus, (Arenaviridae), Macropodid herpesvirus (Herpesviridae),Madrid virus, (Bunyaviridae), Maguari virus, (Bunyaviridae), Main Drainvirus, (Bunyaviridae), Malakal virus, (Rhabdoviridae), Malignantcatarrhal fever virus of European cattle, (Herpesviridae), MalpaisSpring virus, (Rhabdoviridae), Malva silvestris virus, (Rhabdoviridae),Manawa virus, (Bunyaviridae), Manawatu virus, (Nodaviridae), Manitobavirus, (Rhabdoviridae), Manzanilla virus, (Bunyaviridae), Map turtleherpesvirus, (Herpesviridae), Mapputta virus, (Bunyaviridae), Maprikvirus, (Bunyaviridae), Maraba virus, (Rhabdoviridae), Marburg virus,(Filoviridae), Marco virus, (Rhabdoviridae), Marek's diseaseherpesvirus, (Herpesviridae), Marituba virus, (Bunyaviridae), Marmodidherpesvirus, (Herpesviridae), Marmoset cytomegalovirus, (Herpesviridae),Marmoset herpesvirus, (Herpesviridae), Marmosetpox virus, (Poxviridae),Marrakai virus, (Reoviridae), Mason-Pfizer monkey virus, (Retroviridae),Masou salmon reovirus, (Reoviridae), Matruh virus, (Bunyaviridae),Matucare virus, (Reoviridae), Mayaro virus, (Togaviridae), Mboke virus,(Bunyaviridae), Meaban virus, (Flaviviridae), Measles (Edmonston) virus,(Paramyxoviridae), Medical Lake macaque herpesvirus, (Herpesviridae),Melanoplus sanguinipes entomopoxvirus, (Poxviridae), Melao virus,(Bunyaviridae), Meleagrid herpesvirus, (Herpesviridae), Melilotus latentvirus, (Rhabdoviridae), Melolontha melolontha entomopoxvirus,(Poxviridae), Mengovirus, (Picornaviridae), Mermet virus,(Bunyaviridae), Mice minute virus, (Parvoviridae), Mice pneumotropicvirus, (Papovaviridae), Microtus pennsylvanicus herpesvirus,(Herpesviridae), Middelburg virus, (Togaviridae), Miller's nodule virus,(Poxviridae), Mill Door virus, (Reoviridae), Minatitlan virus,(Bunyaviridae), Mink calicivirus, (Caliciviridae), Mink enteritis virus,(Parvoviridae), Minnal virus, (Reoviridae), Mirabilis mosaic virus,Caulimovirus, Mirim virus, (Bunyaviridae), Mitchell river virus,(Reoviridae), Mobala virus, (Arenaviridae), Modoc virus, (Flaviviridae),Moju virus, (Bunyaviridae), Mojui dos Campos virus, (Bunyaviridae),Mokola virus, (Rhabdoviridae), Molluscum contagiosum virus,(Poxviridae), Molluscum-likepox virus, (Poxviridae), Moloney murinesarcoma virus, (Retroviridae), Moloney virus, (Retroviridae), Monkey poxvirus, (Poxviridae), Mono Lake virus, (Reoviridae), Montana myotisleukoencephalitis virus, (Flaviviridae), Monte Dourado virus,(Reoviridae), Mopeia virus, (Arenaviridae), Moriche virus,(Bunyaviridae), Mosqueiro virus, (Rhabdoviridae), Mossuril virus,(Rhabdoviridae), Mount Elgon bat virus, (Rhabdoviridae), Mousecytomegalovirus, (Herpesviridae), Mouse Elberfield virus,(Picornaviridae), Mouse herpesvirus strain, (Herpesviridae), Mousemammary tumor virus, (Retroviridae), Mouse thymic herpesvirus,(Herpesviridae), Movar herpesvirus, (Herpesviridae), Mucambo virus,(Togaviridae), Mudjinbarry virus, (Reoviridae), Muir Springs virus,(Rhabdoviridae), Mule deerpox virus, (Poxviridae), Multimammate mousepapillomavirus, (Papovaviridae), Mumps virus, (Paramyxoviridae), Muridherpesvirus, (Herpesviridae), Murine adenovirus, (Adenoviridae), Zmurine adenovirus, (Adenoviridae), Murine hepatitis virus,(Coronaviridae), Murine herpesvirus, (Herpesviridae), Murine leukemiavirus, (Retroviridae), Murine parainfluenza virus, (Paramyxoviridae),Murine poliovirus, (Picornaviridae), Murine polyomavirus,(Papovaviridae), Murray Valley encephalitis virus, (Flaviviridae), Murrevirus, (Bunyaviridae), Murutucu virus, (Bunyaviridae), Mykines virus,(Reoviridae), Mynahpox virus, (Poxviridae), Myxoma virus, (Poxviridae),Nairobi sheep disease virus, (Bunyaviridae), Naranjal virus,(Flaviviridae), Nasoule virus, (Rhabdoviridae), Navarro virus,(Rhabdoviridae), Ndelle virus, (Reoviridae), Ndumu virus, (Togaviridae),Neckar river virus, (Tombusviridae), Negishi virus, (Flaviviridae),Nelson Bay virus, New Minto virus, (Rhabdoviridae), Newcastle diseasevirus, (Paramyxoviridae), Ngaingan virus, (Rhabdoviridae), Ngari virus,(Bunyaviridae), Ngoupe virus, (Reoviridae), Nile crocodilepox virus,(Poxviridae), Nique virus, (Bunyaviridae), Nkolbisson virus,(Rhabdoviridae), Nola virus, (Bunyaviridae), North Clett virus,(Reoviridae), North End virus, (Reoviridae), Northern cereal mosaicvirus, (Rhabdoviridae), Northern pike herpesvirus, (Herpesviridae),Northway virus, (Bunyaviridae), NorwaLk virus, (Caliciviridae), Ntayavirus, (Flaviviridae), Nugget virus, (Reoviridae), Nyabira virus,(Reoviridae), Nyamanini virus, Unassigned, Nyando virus, (Bunyaviridae),Oak-Vale virus, (Rhabdoviridae), Obodhiang virus, (Rhabdoviridae),Oceanside virus, (Bunyaviridae), Ockelbo virus, (Togaviridae),Odrenisrou virus, (Bunyaviridae), Oedaleus senegalensis entomopoxvirus,(Poxviridae), Oita virus, (Rhabdoviridae), Okhotskiy virus,(Reoviridae), Okola virus, (Bunyaviridae), Olifantsvlei virus,(Bunyaviridae), Omo virus, (Bunyaviridae), Omsk hemorrhagic fever virus,(Flaviviridae), Onchorhynchus masou herpesvirus, (Herpesviridae),O'nyong-nyong virus, (Togaviridae), Operophtera brurnata entomopoxvirus,(Poxviridae), Orangutan herpesvirus, (Herpesviridae), Orf virus,(Poxviridae), Oriboca virus, (Bunyaviridae), Oriximina virus,(Bunyaviridae), Oropouche virus, (Bunyaviridae), Orungo virus,(Reoviridae), Oryctes rhinoceros virus, Unassigned, Ossa virus,(Bunyaviridae), Ouango virus, (Rhabdoviridae), Oubi virus,(Bunyaviridae), Ourem virus, (Reoviridae), Ovine adeno-associated virus,(Parvoviridae), Ovine adenoviruses, (Adenoviridae), (Astroviridae),Ovine herpesvirus, (Herpesviridae), Ovine pulmonary adenocarcinomavirus, (Retroviridae), Owl hepatosplenitis herpesvirus, (Herpesviridae),P virus, (Bunyaviridae), Pacheco's disease virus, (Herpesviridae),Pacora virus, (Bunyaviridae), Pacui virus, (Bunyaviridae), Pahayokeevirus, (Bunyaviridae), Palestina virus, (Bunyaviridae), Palyam virus,(Reoviridae), Pan herpesvirus, (Herpesviridae), Papio Epstein-Barrherpesvirus, (Herpesviridae), Para virus, (Bunyaviridae), Pararnushirvirus, (Bunyaviridae), Parana virus, (Arenaviridae), Parapoxvirus of reddeer in New Zealand, (Poxviridae), Paravaccinia virus, (Poxviridae),Parma wallaby herpesvirus, (Herpesviridae), Paroo river virus,(Reoviridae), Parrot herpesvirus, (Herpesviridae), Parry Creek virus,(Rhabdoviridae), Pata virus, (Reoviridae), Pates monkey herpesvirus pHdelta, (Herpesviridae), Pathum Thani virus, (Bunyaviridae), Patoisvirus, (Bunyaviridae), Peaton virus, (Bunyaviridae), Percid herpesvirus,(Herpesviridae), Perdicid herpesvirus, (Herpesviridae), Perinet virus,(Rhabdoviridae), Peripianata fuliginosa densovirus, (Parvoviridae),Peste-des-petits-ruminants virus, (Paramyxoviridae), Petevo virus,(Reoviridae), Phalacrocoracid herpesvirus, (Herpesviridae), Pheasantadenovirus, (Adenoviridae), Phnom-Penh bat virus, (Flaviviridae), Phocidherpesvirus, (Herpesviridae), Phocine (seal) distemper virus,(Paramyxoviridae), Pichinde virus, (Arenaviridae), Picola virus,(Reoviridae), Pieris rapae densovirus, (Parvoviridae), Pigeonherpesvirus, (Herpesviridae), Pigeonpox virus, (Poxviridae), BadnavirusPiry virus, (Rhabdoviridae), Pisum virus, (Rhabdoviridae), Pixuna virus,(Togaviridae), Playas virus, (Bunyaviridae), Pleuronectid herpesvirus,(Nerpesviridae), Pneumonia virus of mice, (Paramyxoviridae), Pongineherpesvirus, (Herpesviridae), Pongola virus, (Bunyaviridae), Pontevesvirus, (Bunyaviridae), Poovoot virus, (Reoviridae), Porcineadenoviruses, (Adenoviridae), Porcine astrovirus, (Astroviridae),Porcine circovirus, Circoviridae, Porcine enteric calicivirus,(Caliciviridae), Porcine enterovirus, (Picornaviridae), Porcine epidemicdiarrhea virus, (Coronaviridae), Porcine hemagglutinatingencephalomyelitis virus, (Coronaviridae), Porcine parvovirus,(Parvoviridae), Porcine respiratory and reproductive syndrome,(Arterivirus), Porcine rubulavirus, (Paramyxoviridae), Porcinetransmissible gastroenteritis virus, (Coronaviridae), Porcine type Concovirus, (Retroviridae), Porton virus, (Rhabdoviridae), Potosi virus,(Bunyaviridae), Powassan virus, (Flaviviridae), Precarious Point virus,(Bunyaviridae), Pretoria virus, (Bunyaviridae), Primate calicivirus,(Caliciviridae), Prospect Hill virus, (Bunyaviridae), Pseudaletiaincludens densovirus, (Parvoviridae), Pseudocowpox virus, (Poxviridae),Pseudolumpy skin disease virus, (Herpesviridae), Pseudorabies virus,(Herpesviridae), Psittacid herpesvirus, (Herpesviridae), Psittacinepoxvirus, (Poxviridae), Puchong virus, (Rhabdoviridae), Pueblo Viejo virus,(Bunyaviridae), Puffin Island virus, (Bunyaviridae), Punta Salinasvirus, (Bunyaviridae), Punta Toro virus, (Bunyaviridae), Purus virus,(Reoviridae), Puumala virus, (Bunyaviridae), Qalyub virus,(Bunyaviridae), Quailpox virus, (Poxviridae), Quokkapox virus,(Poxviridae), Rabbit coronavirus, (Coronaviridae), Rabbit fibroma virus,(Poxviridae), Rabbit hemorrhagic disease virus, (Caliciviridae), Rabbitkidney vacuolating virus, (Papovaviridae), Rabbit oral papillomavirus,(Papovaviridae), Rabbitpox virus, (Poxviridae), Rabies virus,(Rhabdoviridae), Raccoon parvovirus, (Parvoviridae), Raccoonpox virus,(Poxviridae), Radi virus, (Rhabdoviridae), Rangifer tarandusherpesvirus, (Herpesviridae), Ranid herpesvirus, (Herpesviridae),Raphanus virus, (Rhabdoviridae), Rat coronavirus, (Coronaviridae), Ratcytomegalovirus, (Herpesviridae), Rat virus, R, (Parvoviridae), Razavirus, (Bunyaviridae), Razdan virus, (Bunyaviridae), Red deerherpesvirus, (Herpesviridae), Red kangaroopox virus, (Poxviridae), ReedRanch virus, (Rhabdoviridae), herpesvirus, (Herpesviridae), Reindeerpapillomavirus, (Papovaviridae), Reptile calicivirus, (Caliciviridae),Resistencia virus, (Bunyaviridae), Restan virus, (Bunyaviridae),Reticuloendotheliosis virus, (Retroviridae), Rhesus HHV-like virus,(Herpesviridae), Rhesus leukocyte associated herpesvirus strain,(Herpesviridae), Rhesus monkey cytomegalovirus, (Herpesviridae), Rhesusmonkey papillomavirus, (Papovaviridae), Rheumatoid arthritis virus,(Parvoviridae), Rift Valley fever virus, (Bunyaviridae), Rinderpestvirus, (Paramyxoviridae), Rio Bravo virus, (Flaviviridae), Rio Grandevirus, (Bunyaviridae), RML virus, (Bunyaviridae), Rochambeau virus,(Rhabdoviridae), Rocio virus, (Flaviviridae), Ross River virus,(Togaviridae), Rost Islands virus, (Reoviridae), Rous sarcoma virus,(Retroviridae), Royal farm virus, (Flaviuiridae), RT parvovirus,(Parvoviridae), Rubella virus, (Togaviridae), Russian spring summerencephalitis virus, (Flaviviridae), S-virus, (Reoviridae), SA virus,(Herpesviridae), Sabio virus, (Arenaviridae), Sabo virus,(Bunyaviridae), Saboya virus, (Flaviviridae), Sacbrood virus,(Picornaviridae), Sagiyama virus, (Togaviridae), Saimiriine herpesvirus,(Herpesviridae), SaintAbb's Head virus, (Reoviridae), Saint-Florisvirus, (Bunyaviridae), Sakhalin virus, (Bunyaviridae), Sal Vieja virus,(Flaviviridae), Salanga virus, (Bunyaviridae), Salangapox virus,(Poxviridae), Salehabad virus, (Bunyaviridae), Salmonid herpesvirus,(Herpesviridae), Salmonis virus, (Rhabdoviridae), Sambucus vein clearingvirus, (Rhabdoviridae), SanAngelo virus, (Bunyaviridae), San Juan virus,(Bunyaviridae), San Miguel sealion virus, (Caliciviridae), San Perlitavirus, (Flaviviridae), Sand rat nuclear inclusion agents,(Herpesviridae), Sandfly fever Naples virus, (Bunyaviridae), Sandflyfever Sicilian virus, (Bunyaviridae), Sandjimba virus, (Rhabdoviridae),Sango virus, (Bunyaviridae), Santa Rosa virus, (Bunyaviridae), Santaremvirus, (Bunyaviridae), Sapphire II virus, (Bunyaviridae), Saraca virus,(Reoviridae), Sarracenia purpurea virus, (Rhabdoviridae), Sathuperivirus, (Bunyaviridae), Saumarez Reef virus, (Flaviviridae), Sawgrassvirus, (Rhabdoviridae), Schistocerca gregaria entomopoxvirus,(Poxviridae), Sciurid herpesvirus, (Herpesviridae), Sciurid herpesvirus,(Herpesviridae), Sealpox virus, (Poxviridae), Seletar virus,(Reoviridae) Semliki Forest virus, (Togaviridae), Sena Madureira virus,(Rhabdoviridae), Sendai virus, (Paramyxoviridae), Seoul Virus,(Bunyaviridae), Sepik virus, (Flaviviridae), Serra do Navio virus,(Bunyaviridae), Shamonda virus, (Bunyaviridae), Shark River virus,(Bunyaviridae), Sheep associated malignant catarrhal fever of,(Herpesviridae), Sheep papillomavirus, (Papovaviridae), Sheep pulmonaryadenomatosis associated herpesvirus, (Herpesviridae), Sheeppox virus,(Poxviridae), Shiant Islands virus, (Reoviridae), Shokwe virus,(Bunyaviridae), Shope fibroma virus, (Poxviridae), Shuni virus,(Bunyaviridae), Sibine fusca densovirus, (Parvoviridae), Sigma virus,(Rhabdoviridae), Sikte water-borne virus, (Tombusviridae), Silverwatervirus, (Bunyaviridae), virus, (Bunyaviridae), Simian adenoviruses,(Adenoviridae), Simian agent virus, (Papovaviridae), Simian enterovirus,(Picornaviridae), Simian foamy virus, (Retroviridae), Simian hemorrhagicfever virus, (Arterivirus), Simian hepatitis A virus, (Picornaviridae),Simian immunodeficiency virus, (Retroviridae), Simian parainfluenzavirus, (Paramyxoviridae), Simian rotavirus SA, (Reoviridae), Simiansarcoma virus, (Retroviridae), Simian T-lymphotropic virus,(Retroviridae), Simian type D virus, (Retroviridae), Simian vancellaherpesvirus, (Herpesviridae), Simian virus, (Papovaviridae), Simuliumvittatum densovirus, (Parvoviridae), Sindbis virus, (Togaviridae),Sixgun city virus, (Reoviridae), Skunkpox virus, (Poxviridae), Smeltreovirus, (Reoviridae), Snakehead rhabdovirus, (Rhabdoviridae), Snowshoehare virus, (Bunyaviridae), Snyder-Theilen feline sarcoma virus,(Retroviridae), Sofyn virus, (Flaviviridae), Sokoluk virus,(Flaviviridae), Soldado virus, (Bunyaviridae), Somerville virus,(Reoviridae), Sparrowpox virus, (Poxviridae), Spectacled caimanpoxvirus, (Poxviridae), SPH virus, (Arenaviridae), Sphenicid herpesvirus,(Herpesviridae), Spider monkey herpesvirus, (Herpesviridae), Spondwenivirus, (Flaviviridae), Spring viremia of carp virus, (Rhabdoviridae),Squirrel fibroma virus, (Poxviridae), Squirrel monkey herpesvirus,(Herpesviridae), Squirrel monkey retrovirus, (Retroviridae), SR-virus,(Bunyaviridae), Sripur virus, (Rhabdoviridae), StAbbs Head virus,(Bunyaviridae), St. Louis encephalitis virus, (Flaviviridae),Starlingpox virus, (Poxviridae), Stratford virus, (Flaviviridae),Strigid herpesvirus, (Herpesviridae), Striped bass reovirus,(Reoviridae), Striped Jack nervous necrosis virus, (Nodaviridae),Stump-tailed macaque virus, (Papovaviridae), Suid herpesvirus,(Herpesviridae), Sunday Canyon virus, (Bunyaviridae), Sweetwater Branchvirus, (Rhabdoviridae), Swine cytomegalovirus, (Herpesviridae), Swineinfertility and respiratory syndrome virus, (Arterivirus), Swinepoxvirus, (Poxviridae), Tacaiuma virus, (Bunyaviridae), Tacaribe virus,(Arenaviridae), Taggart virus, (Bunyaviridae), Tahyna virus,(Bunyaviridae), Tai virus, (Bunyaviridae), Taiassui virus,(Bunyaviridae), Tamana bat virus, (Flaviviridae), Tamdy virus,(Bunyaviridae), Tamiami virus, (Arenaviridae), Tanapox virus,(Poxviridae), Tanga virus, (Bunyaviridae), Tanjong Rabok virus,(Bunyaviridae), Taro bacilliform virus, (Badnavirus), Tataguine virus,(Bunyaviridae), Taterapox virus, (Poxviridae), Tehran virus,(Bunyaviridae), Telok Forest virus, (Bunyaviridae), Tembe virus,(Reoviridae), Tembusu virus, (Flaviviridae), Tench reovirus,(Reoviridae), Tensaw virus, (Bunyaviridae), Tephrosia symptomless virus,(Tombusviridae), Termeil virus, (Bunyaviridae), Tete virus,(Bunyaviridae), Thailand virus, (Bunyaviridae), Theiler's murineencephalomyelitis virus, (Picornaviridae), Thermoproteus virus,Lipothrixviridae, Thiafora virus, (Bunyaviridae), Thimiri virus,(Bunyaviridae), Thogoto virus, (Orthomyxoviridae), Thormodseyjarkletturvirus, (Reoviridae), Thottapalayam virus, (Bunyaviridae), Tibrogarganvirus, (Rhabdoviridae), Tick-borne encephalitis virus, (Flaviviridae),Tillamook virus, (Bunyaviridae), Tilligerry virus, (Reoviridae), Timbovirus, (Rhabdoviridae), Tilmboteua virus, (Bunyaviridae), Tilmaroovirus, (Bunyaviridae), Tindholmur virus, (Reoviridae), Tlacotalpanvirus, (Bunyaviridae), Toscana virus, (Bunyaviridae),Tradescantia/Zebrina virus, Potyviridae, Trager duck spleen necrosisvirus, (Retroviridae), Tree shrew adenovirus, (Adenoviridae), Tree shrewherpesvims, (Herpesviridae), Triatoma virus, (Picornaviridae), Tribecvirus, (Reoviridae), Trivittatus virus, (Bunyaviridae), Trombetas virus,(Bunyaviridae), Trubanarnan virus, (Bunyaviridae), Tsuruse virus,(Bunyaviridae), Tucunduba virus, (Bunyaviridae), Tumor virus X,(Parvoviridae), Tupaia virus, (Rhabdoviridae), Tupaiid herpesvirus,(Herpesviridae), Turbot herpesvirus, (Herpesviridae), Turbot reovirus,(Reoviridae), Turkey adenoviruses, (Adenoviridae), Turkey coronavirus,(Coronaviridae), Turkey herpesvirus, (Herpesviridae), Turkeyrhinotracheitis virus, (Paramyxoviridae), Turkeypox virus, (Poxviridae),Turlock virus, (Bunyaviridae), Turuna virus, (Bunyaviridae), Tyuleniyvirus, (Flaviviridae) Uasin Gishu disease virus, (Poxviridae), Uganda Svirus, (Flaviviridae), Ulcerative disease rhabdovirus, (Rhabdoviridae),Umatilla virus, (Reoviridae), Umbre virus, (Bunyaviridae), Una virus,(Togaviridae), Upolu virus, (Bunyaviridae), UR sarcoma virus,(Retroviridae), Urucuri virus, (Bunyaviridae), Usutu virus,(Flaviviridae), Uting a virus, (Bunyaviridae), Utive virus,(Bunyaviridae), Uukuniemi virus, (Bunyaviridae) Vaccinia subspecies,(Poxviridae), Vaccinia virus, (Poxviridae), Vaeroy virus, (Reoviridae),Varicella-zoster virus, (Herpesviridae), Variola virus, (Poxviridae),Vellore virus, (Reoviridae), Venezuelan equine encephalitis virus,(Togaviridae), Vesicular exanthema of swine virus, (Caliciviridae),Vesicular stomatitis Alagoas virus, Rkabdoviridae, Vesicular stomatitisIndiana virus, (Rhabdoviridae), Vesicular stomatitis New Jersey virus,(Rhabdoviridae), Vilyuisk virus, (Picornaviridae), Vinces virus,(Bunyaviridae), Viper retrovirus, (Retroviridae), Viral hemorrhagicsepticemia virus, (Rhabdoviridae), Virgin River virus, (Bunyaviridae),Virus III, (Herpesviridae), Visna/maedi virus, (Retroviridae),Volepoxvirus, (Poxviridae), Wad Medani virus, (Reoviridae), Wallalvirus, (Reoviridae), Walleye epidermal hyperplasia, (Herpesviridae),Wanowrie virus, (Bunyaviridae), Warrego virus, (Reoviridae), Weddelwater-borne virus, Tombusviridae, Weldona virus, (Bunyaviridae),Wesselsbron virus, (Flaviviridae), West Nile virus, (Flaviviridae),Western equine encephalitis virus, (Togaviridae), Wexford virus,(Reoviridae), Whataroa virus, (Togaviridae), Wildbeest herpesvirus,(Herpesviridae), Witwatersrand virus, (Bunyaviridae), Wongal virus,(Bunyaviridae), Wongorr virus, (Reoviridae), Woodchuck hepatitis Bvirus, (Hepadnaviridae), Woodchuck herpesvirus marmota, (Herpesviridae),Woolly monkey sarcoma virus, (Retroviridae), Wound tumor virus,(Reoviridae), WVU virus, (Reoviridae), WW virus, (Reoviridae), Wyeomyiavirus, (Bunyaviridae), Xiburema virus, (Rhabdoviridae), Xingu virus,(Bunyaviridae), Y sarcoma virus, (Retroviridae), Yaba monkey tumorvirus, (Poxviridae), Yaba-virus, (Bunyaviridae), Yaba-virus,(Bunyaviridae), Yacaaba virus, (Bunyaviridae), Yaounde virus,(Flaviviridae), Yaquina Head virus, (Reoviridae), Yata virus,(Rhabdoviridae), Yellow fever virus, (Flaviviridae), Yogue virus,(Bunyaviridae), Yokapox virus, (Poxviridae), Yokase virus,(Flaviviridae), Yucca baciliform virus, Badnavirus, Yug Bogdanovacvirus, (Rhabdoviridae), Zaliv Terpeniya virus, (Bunyaviridae), Zea maysvirus, (Rhabdoviridae), Zegla virus, (Bunyaviridae), Zika virus,(Flaviviridae), Zirqa virus, (Bunyaviridae).

Pathogenic Infections

In a preferred embodiment the pathogen is an intracellular pathogen,i.e. a pathogen capable of growing and reproducing inside the cells of ahost. Bacterial examples which may be prevented and/or treated by thecompositions and methods of the disclosure include but are not limitedto Francisella tularensis, Listeria monocytogenes, Salmonella, Brucella,Legionella, Mycobacterium, Nocardia, Rhodococcus equi, Yersinia,Neisseria meningitidis, Chlamydia, Rickettsia, Coxiella, Mycobacterium,such as Mycobacterium leprae and Treponema pallidum. Fungal examplesinclude but are not limited to Histoplasma capsulatum, Cryptococcusneoformans and Pneumocystis jirovecii. Examples of protozoa include butare not limited to Apicomplexans (e.g. Plasmodium spp., Toxoplasmagondii and Cryptosporidium parvum) and Trypanosomatids (e.g. Leishmaniaspp. and Trypanosoma cruzi).

The following is an exemplary but non-limiting discussion of variousdisease agents that could be the subject of prevention and/or treatmentin accordance with the present disclosure.

Bacterial Pathogens

There are hundreds of bacterial pathogens in both the Gram-positive andGram-negative families that cause significant illness and mortalityaround the word, despite decades of effort developing antibiotic agents.Antibiotic resistance is a growing problem in bacterial disease.Bacterial pathogens may be prevented and/or treated by the compositionsand methods of the disclosure.

One of the bacterial diseases with highest disease burden istuberculosis, caused by the bacterium Mycobacterium tuberculosis, whichkills about 2 million people a year, mostly in sub-Saharan Africa.Pathogenic bacteria contribute to other globally important diseases,such as pneumonia, which can be caused by bacteria such as Streptococcusand Pseudomonas, and food borne illnesses, which can be caused bybacteria such as Shigella, Campylobacter, and Salmonella. Pathogenicbacteria also cause infections such as tetanus, typhoid fever,diphtheria, syphilis, and leprosy.

Conditionally pathogenic bacteria are only pathogenic under certainconditions, such as a wound facilitates entry of bacteria into theblood, or a decrease in immune function. For example, Staphylococcus orStreptococcus are also part of the normal human flora and usually existon the skin or in the nose without causing disease, but can potentiallycause skin infections, pneumonia, meningitis, and even overwhelmingsepsis, a systemic inflammatory response producing shock, massivevasodilation and death. Some species of bacteria, such as Pseudomonasaeruginosa, Burkholderia cenocepacia, and Mycobacterium avium, areopportunistic pathogens and cause disease mainly in people sufferingfrom immunosuppression or cystic fibrosis.

Other bacteria invariably cause disease in humans, such as obligateintracellular parasites (e.g., Chlamydophila, Ehrlichia, Rickettsia)that are capable of growing and reproducing only within the cells ofother organisms. Still, infections with intracellular bacteria may beasymptomatic, such as during the incubation period. An example ofintracellular bacteria is Rickettsia. One species of Rickettsia causestyphus, while another causes Rocky Mountain spotted fever. Chlamydia,another phylum of obligate intracellular parasites, contains speciesthat can cause pneumonia or urinary tract infection and may be involvedin coronary heart disease. Mycobacterium, Brucella, Francisella,Legionella, and Listeria can exist intracellular, though they arefacultative (not obligate) intracellular parasites.

Gram-positive bacteria include Staphylococcus aureus; Staphylococcusepidermidis; Staphylococcus saprophyticus; Streptococcus pyogenes(Lancefield group A, beta-hemolytic); Streptococcus agalactiae(Lancefield group B, beta-hemolytic); Streptococcus Viridans group (mostare alpha-hemolytic) including, for example, the Mitus group (S. mitus,S. sanguis, S. parasanguis, S. gordonii, S. crista, S. infantis, S.oralis, S. peroris), the Salivarius group (S. salivarius, S.vestibularis, S. thermophilus), the Mutans group (S. mutans, S.sobrinus, S. criceti, S. rattus, S. downei, S. macacae), and theAnginosus group (S. anginosus, S. constellatus, S. intermedius);Streptococcus, e.g., S. bovis, S. equinus (Lancefield group D,alpha-hemolytic); Streptococcuspneumoniae (no Lancefield antigen;alpha-hemolytic); Peptostreptococcus and Peptococcus; Entercoccusfaecalis; Enterococcus faeccium; Cornybacterium diphtheria; Bacillusanthracis; Bacillus cereus; Clostridium C. botulinum (more rarely, C.baratii and C. butyricum); Clostridium tetani; Clostridium perfringens;Clostridium difficile; Clostridium sordellii; Listeria monocytogenes;Actinomyces israelii; Nocardia asteroids; Streptomyces.

Gram-negative bacteria include Neisseria meningitides; Neisseriagonorrhoeae; Moraxella (subgenera Branhamella) catarrhalis; Kingella(most commonly kingae); Acinetobacter baumannii, Oligella ureolytica;Oligella urethralis; Escherichia coli; Shigella (S. dysenteriae, S.flexneri, S. boydii, S. sonnei); Salmonella non typhoidal, including S.enterica serotype enteritidis, S. enterica serotype typhimurium, S.enterica serotype Choleraesuis, S. bongori, Salmonella S. entericaserotype Typhi; Yersinia enterocolitica, Klebsiella pneumoniae; Proteusmirabilis; Enterobacter; Cronobacter (formerly called Enterobactersakazakii); Serratia; Edwardsiella; Citrobacter; Hafnia; Providencia;Vibrio cholera; Vibrio parahemolyticus; Campylobacter; Helicobacter(formerly called Campylobacter) pylori, Pseudomonas aeruginosa;Burkholderia cepacia; Burkholderia mallei; Burkholderia pseudomallei;Stenotrophomonas maltophilia; Bacteroides fragilis, Bacteroidesmelaninogenicus; Fusobacterium; Haemophilus influenza; Haemophilusducreyi; Gardnerella (formerly called Haemophilus) vaginalis; Bordetellapertussis; Legionella; Yersinia pestis; Francisella tularensis; BrucellaB. melitensis (infects sheep/goats); B. abortus (abortions in cows); B.suis (pigs); B. canis (dogs); B. maris (marine animals); Pasteurellamultocida; Streptobacillus moniliformis; Spirillum minus; Treponemapallidum; Treponema pallidum subspecies pertenue; Treponema pallidumsubspecies endemicum; Treponema pallidum subspecies carateum; Borreliaburgdorferi; Borrelia; Leptospira; Chlamydia trachomatis; Chlamydiapneumonia; Chlamydia psittaci; Rickettsiae rickettsia; Rickettsiaeakari; Rickettsiae prowazekii; Rickettsiae typhi; Rickettsiaetsutsugamushi; Rickettsiae parkeri; Rickettsiae africae; Rickettsiaconorii; Rickettsia australis; Rickettsia siberica; Rickettsia japonica;Bartonella Quintana; Bartonella henselae; Bartonella bacilliformis;Coxiella burnetii; Ehrlichia; Anaplasma phagocytophilum; Neorickettsia;Orientia; Klebsiella granulomatis (formerly called Calymmatobacteriumgranulomatis); Capnocytophaga.

Other bacteria include Mycobacterium tuberculosis; Mycobacterium bovis;Mycobacterium leprae; Mycobacterium avium-intracellulare or aviumcomplex (MAI or MAC); Mycobacterium ulcerans; Mycobacterium kansasii;Mycobacterium marinum; Mycobacterium scrofulaceum; Mycobacteriumfortuitum; Mycobacterium chelonei; Mycobacterium abscessus; Mycoplasmapneumonia; Ureaplasma urealyticum.

Viral Pathogens

Vaccines may be developed for any viral pathogen for which protectiveantibodies are available. Viruses include DNA and RNA viruses. Theseinclude respiratory viruses such as Adenoviruses, Avian influenza,Influenza virus type A, Influenza virus type B, Measles, Parainfluenzavirus, Respiratory syncytial virus (RSV), Rhinoviruses, and SARScoronavirus, gastro-enteric viruses such as Coxsackie viruses,enteroviruses such as Poliovirus and Rotavirus, hepatitis viruses suchas Hepatitis B virus, Hepatitis C virus, Bovine viral diarrhea virus(surrogate), herpes viruses such as Herpes simplex 1, Herpes simplex 2,Human cytomegalovirus, and Varicella zoster virus, retroviruses such asHuman immunodeficiency virus 1 (HIV-1), and Human immunodeficiency virus2 (HIV-2), as well as Dengue virus, Hantavirus, Hemorrhagic feverviruses, Lymphocytic choriomeningitis virus, Smallpox virus, Ebolavirus, Rabies virus, West Nile virus (WNV) and Yellow fever virus.

Examples of viruses which may be prevented and/or treated by thecompositions and methods of the disclosure include Parvoviridae;Papovaviridae (Human papilloma virus (HPV); BK polyomavirus; JCpolyomavirus); Adenoviridae (Adenovirus, types 40 and 41); Herpesviridae(simplex virus type 1 (HHV-1); Herpes simplex virus type 2 (HHV-2);Macacine herpesvirus 1; Varicella-zoster virus (VZV; HHV-3);Epstein-Barr virus (EBV; HHV-4); Cytomegalovirus (CMV; HHV-5); HumanHerpesvirus 6 (HHV-6); HHV-7; Kaposi's sarcoma-associated herpesvirus(HHV-8); Hepadnaviridae (Hepatitis B virus); Poxviridae (Smallpox(Variola major); Alastrim (Variola minor); Vaccinia; Cowpox; Monkeypox;Goat pox, pseudocowpox virus, bovine papular stomatitis virus, tanapox,volepox and related pox viruses such as avipox, buffalopox, racoonpox,squirrelpox, etc.); Molluscum contagiosum; Picornaviridae (Polio virus;Coxsackie A virus; Coxsackie B; virus; Foot and mouth disease; ECHOvirus; Hepatitis A virus; Rhinovirus); Astroviridae; Caliciviridae(Norwalk virus; Norovirus; Sapoviruses; Hepatitis E virus); Reoviridae(Rotavirus); Togaviridae (Alpha viruses; Western equine encephalitis(WEE) virus; Eastern equine encephalitis (EEE) virus; Venezuelan equineencephalitis (VEE) virus; Chikungunya virus; Rubivirus (rubella));Flaviviridae (Yellow fever virus; Dengue virus; St. Louis encephalitisvirus; Japanese encephalitis virus; Tick-borne encephalitis virus; Omskhemorrhagic fever virus; Al Khumra virus; Kyasanur Forest disease virus;Louping ill virus; West Nile virus; Kunjin virus; Murray Valley fevervirus; Powassan virus; Hepatitis C virus; Hepatitis G virus);Coronoviridae (Respiratory illness (cold); Severe Acute RespiratorySyndrom)-corona virus (SARS-CoV)); Bunyaviridae (California encephalitisvirus; La Crosse virus; Rift Valley fever virus; Phleboviruses; Sandflyfever virus; Nairovirus; Hantavirus); Orthomyxoviridae (Influenza virus(types A, B & C); Paramyxoviridae (Parainfluenza virus; Respiratorysyncytial virus (RSV); Hendra virus disease (formerly equinemorbillivirus); Nipah virus encephalitis; Mumps Measles; Newcastledisease virus); Rhabdoviridae (Rabies virus); Filoviridae (Marburg virus(acute hemorrhagic fever); Ebola virus (acute hemorrhagic fever));Arenaviridae (Lymphocytic choriomeningitis virus; Lassa fever virus;Lujo virus; Chapare virus; Junin virus; Machupo virus; Guanarito virus;Sabia virus); Retroviridae (Human Immunodeficiency virus (HIV) types Iand II; Human T-cell leukemia virus (HLTV) type I; Human T-cell leukemiavirus (HLTV) type II; Spumaviruses; Xenotropic murine leukemiavirus-related (XMRV).

Fungal Pathogens

Pathogenic fungi are fungi that cause disease in humans or otherorganisms. The pathogenic fungi which may be prevented and/or treated bythe compositions and methods of the disclosure include but are notlimited to the following.

Candida species are important human pathogens that are best known forcausing opportunist infections in immunocompromised hosts (e.g.,transplant patients, AIDS sufferers, and cancer patients). Infectionsare difficult to treat and can be very serious. Aspergillus can and doescause disease in three major ways: through the production of mycotoxins;through induction of allergenic responses; and through localized orsystemic infections. With the latter two categories, the immune statusof the host is pivotal. The most common pathogenic species areAspergillus fumigatus and Aspergillus flavus. Cryptococcus neoformanscan cause a severe form of meningitis and meningo-encephalitis inpatients with HIV infection and AIDS. The majority of Cryptococcusspecies lives in the soil and do not cause disease in humans.Cryptococcus laurentii and Cryptococcus albidus have been known tooccasionally cause moderate-to-severe disease in human patients withcompromised immunity. Cryptococcus gattii is endemic to tropical partsof the continent of Africa and Australia and can cause disease innon-immunocompromised people. Histoplasma capsulatum can causehistoplasmosis in humans, dogs and cats. Pneumocystis jirovecii (orPneumocystis carinii) can cause a form of pneumonia in people withweakened immune systems, such as premature children, the elderly,transplant patients and AIDS patients. Stachybotrys chartarum or “blackmold” can cause respiratory damage and severe headaches. It frequentlyoccurs in houses in regions that are chronically damp.

Examples include Malassezia furfur; Exophiala werneckii; Microsporumspecies; Trichophyton species; Epidermophyton floccosum; Sporothrixschenckii; Phialophora verrucosa; Cladosporium carrinonii; Fonsecaeaspecies; Coccidioides; Histoplasma capsulatum; Blastomyces dermatitidis;Cryptococcus neoformans; Cryptococcus gattii; Candida albicans;Aspergillus fumigatus; Aspergillus flavus; Aspergillus niger; Rhizopus;Rhizomucor; Mucor; Exserohilum.

Parasites

Parasite presents a major health issue, particularly in under-developedcountries around the world. Significant pathogenic parasites which maybe prevented and/or treated by the compositions and methods of thedisclosure include worms (roundworms, flatworms) and protozoa. Entamoebahistolytica; Giardia lamblia; Trichomonas vaginalis; Plasmodiumfalciparum; Plasmodium malariae; Plasmodium ovale; Plasmodium vivax;Trypanosoma cruzi; Ascaris lumbricoides; Trichinella spiralis;Toxoplasma gondii; Leishmania donovani; Leishmania tropica; Leishmaniabraziliensis; Schistosoma mansoni; Schistosoma japonicum; Schistosomahaematobium; Cyclospora cayetanesis; Crytosporidium, e.g., C. parvum, C.hominis; Cystoisospora species (formerly called Isospora species), e.g.,C. belli; Naegleria fowleri; Acanthamoeba species; Sappinia diploidea;Sappinia pedata; Balamuthia mandrillaris; Pneumocystis jiroveci(formerly called Pneumocystis carinii); Plasmodium knowlesi; Babesiamicroti; Babesia divergens; Babesia duncani; Babesia (no species nameyet but designated MO-1); Trypanosoma brucei rhodesiense; Trypanosomabrucei gambiense; Balantidium coli; Dientamoeba fragilis; Phylum:Microsporidia; Sarcocystis; Baylisascaris; Necator americanus;Ancylostoma duodenale; Strongloides stercoralis; Trichinellapseudospiralis; Trichinella nelsoni; Trichinella britovi; Trichinellanativa; Trichuris trichiura; Enterobius vermicularis; Anisakis simplex;Pseudoterranova decipiens; Trichostrongylus; Oesophagostomum, e.g., O.bifurcom; Angiostrongylus; Capillaria; Dirofilaria; Loa boa; Onchocercavolvulus; Wuchereria bancrofti; Brugia malayi; Brugia timori;Mansonella, M. perstans; M. streptocerca; M. ozzardi; Dracunculusmediensis; Cutaneous larva migrans (commonly Ancylostoma braziliense=doghookworm; also A. caninum, A. ceylanicum, and Uncinaria stenocephala);Visceral larva migrans (most commonly Toxocara canis=dog roundworm, lesscommonly Toxocara cati=cat roundworm, Baylisascaris procyonis=raccoonroundworm) or ocular larva migrans or neural larva migrans (B.procyonis); Gnathostoma G. spinigerum and G. hispidum; Dicrocoeliumdendriticum; Echinostoma, e.g., E. hortense, E. macrorchis, E.revolutum, E. ilocanu, and E. perfoliatum; Thelazia; Shistosomajaponicum; Shistosoma mansoni; Shistosoma haematobium; Shistosomaintercalatum; Shistosoma mekongi; Austrobilharzia variglandis and otherschistosomes; Taenia solium; Taenia saginata; Taenia multiceps; Taeniaserialis; Taenia asiatica; Diphyllobothrium latum; Hymenolepsis nana;Echinoccoccus; Paragonimus; Clonorchis sinensis; Dipylidium caninum;Fasciola, F. hepatica; F. gigantica; Fasciolopsis buski; Heterophyesheterophyes; Hymenolepsis, H. nana, H. dimnuta; Opisthorchis; Bertiella,e.g., B. studeri and B. mucronata; Macracanthorhynchus hirudinaceous;Moniliformis moniliformis; Bolbosoma species; Metagonimus yokogawai;Dioctophyme renale; Mesocestoides, e.g., M. lineatus and M. variabilis;Philophthalmus, e.g., P. lacrymosus, P. gralli, P. palpebrarum;Spirometra, e.g., S. mansoni, S. ranarum, S. mansonoides, S. erinacei;Sparganum proliferum.

Pharmaceutical Dosage Forms

The compositions of the present disclosure can be processed byagglomeration, air suspension chilling, air suspension drying, balling,coacervation, coating, comminution, compression, cryopelletization,encapsulation, extrusion, wet granulation, dry granulation,homogenization, inclusion complexation, lyophilization, melting,microencapsulation, mixing, molding, pan coating, solvent dehydration,sonication, spheronization, spray chilling, spray congealing, spraydrying, or other processes known in the art. The compositions can beprovided in the form of a minicapsule, a capsule, a tablet, an implant,a troche, a lozenge (minitablet), a temporary or permanent suspension,an ovule, a suppository, a wafer, a chewable tablet, a quick or fastdissolving tablet, an effervescent tablet, a buccal or sublingual solid,a granule, a film, a sprinkle, a pellet, a bead, a pill, a powder, atriturate, a platelet, a strip or a sachet. Compositions can also beadministered as a “dry syrup”, where the finished dosage form is placeddirectly on the tongue and swallowed or followed with a drink orbeverage. These forms are well known in the art and are packagedappropriately. The compositions can be formulated for oral, nasal,buccal, ocular, urethral, transmucosal, vaginal, topical or rectaldelivery.

The pharmaceutical composition can be coated with one or more entericcoatings, seal coatings, film coatings, barrier coatings, compresscoatings, fast disintegrating coatings, or enzyme degradable coatings.Multiple coatings can be applied for desired performance. Further, thedosage form can be designed for immediate release, pulsatile release,controlled release, extended release, delayed release, targeted release,synchronized release, or targeted delayed release. Forrelease/absorption control, solid carriers can be made of variouscomponent types and levels or thicknesses of coats, with or without anactive ingredient. Such diverse solid carriers can be blended in adosage form to achieve a desired performance. The definitions of theseterms are known to those skilled in the art. In addition, the dosageform release profile can be affected by a polymeric matrix composition,a coated matrix composition, a multiparticulate composition, a coatedmultiparticulate composition, an ion-exchange resin-based composition,an osmosis-based composition, or a biodegradable polymeric composition.Without wishing to be bound by theory, it is believed that the releasemay be effected through favorable diffusion, dissolution, erosion,ion-exchange, osmosis or combinations thereof.

When formulated as a capsule, the capsule can be a hard or soft gelatincapsule, a starch capsule, or a cellulosic capsule. Although not limitedto capsules, such dosage forms can further be coated with, for example,a seal coating, an enteric coating, an extended release coating, or atargeted delayed release coating. These various coatings are known inthe art, but for clarity, the following brief descriptions are provided:seal coating, or coating with isolation layers: Thin layers of up to 20microns in thickness can be applied for variety of reasons, includingfor particle porosity reduction, to reduce dust, for chemicalprotection, to mask taste, to reduce odor, to minimize gastrointestinalirritation, etc. The isolating effect is proportional to the thicknessof the coating. Water soluble cellulose ethers are preferred for thisapplication. HPMC and ethyl cellulose in combination, or Eudragit E100,may be particularly suitable for taste masking applications. Traditionalenteric coating materials listed elsewhere can also be applied to forman isolating layer.

Extended release coatings are designed to effect delivery over anextended period of time. The extended release coating is apH-independent coating formed of, for example, ethyl cellulose,hydroxypropyl cellulose, methylcellulose, hydroxymethyl cellulose,hydroxyethyl cellulose, acrylic esters, or sodium carboxymethylcellulose. Various extended release dosage forms can be readily designedby one skilled in art to achieve delivery to both the small and largeintestines, to only the small intestine, or to only the large intestine,depending upon the choice of coating materials and/or coating thickness.

Enteric coatings are mixtures of pharmaceutically acceptable excipientswhich are applied to, combined with, mixed with or otherwise added tothe carrier or composition. The coating may be applied to a compressedor molded or extruded tablet, a gelatin capsule, and/or pellets, beads,granules or particles of the carrier or composition. The coating may beapplied through an aqueous dispersion or after dissolving in appropriatesolvent. Additional additives and their levels, and selection of aprimary coating material or materials will depend on the followingproperties: 1. resistance to dissolution and disintegration in thestomach; 2. impermeability to gastric fluids and drug/carrier/enzymewhile in the stomach; 3. ability to dissolve or disintegrate rapidly atthe target intestine site; 4. physical and chemical stability duringstorage; 5. non-toxicity; 6. easy application as a coating (substratefriendly); and 7. economical practicality.

Dosage forms of the compositions of the present disclosure can also beformulated as enteric coated delayed release oral dosage forms, i.e., asan oral dosage form of a pharmaceutical composition as described hereinwhich utilizes an enteric coating to affect release in the lowergastrointestinal tract. The enteric coated dosage form may be acompressed or molded or extruded tablet/mold (coated or uncoated)containing granules, pellets, beads or particles of the activeingredient and/or other composition components, which are themselvescoated or uncoated. The enteric coated oral dosage form may also be acapsule (coated or uncoated) containing pellets, beads or granules ofthe solid carrier or the composition, which are themselves coated oruncoated.

Delayed release generally refers to the delivery so that the release canbe accomplished at some generally predictable location in the lowerintestinal tract more distal to that which would have been accomplishedif there had been no delayed release alterations. The preferred methodfor delay of release is coating. Any coatings should be applied to asufficient thickness such that the entire coating does not dissolve inthe gastrointestinal fluids at pH below about 5, but does dissolve at pHabout 5 and above. It is expected that any anionic polymer exhibiting apH-dependent solubility profile can be used as an enteric coating in thepractice of the present disclosure to achieve delivery to the lowergastrointestinal tract. Polymers for use in the present disclosure areanionic carboxylic polymers.

Shellac, also called purified lac, a refined product obtained from the,resinous secretion of an insect. This coating dissolves in media ofpH >7. Colorants, detackifiers, surfactants, antifoaming agents,lubricants, stabilizers such as hydroxy propyl cellulose, acid/base maybe added to the coatings besides plasticizers to solubilize or dispersethe coating material, and to improve coating performance and the coatedproduct.

In carrying out the method of the present disclosure, the combination ofthe disclosure may be administered to mammalian species, such as dogs,cats, humans, etc. and as such may be incorporated in a conventionalsystemic dosage form, such as a tablet, capsule, elixir or injectable.The above dosage forms will also include the necessary carrier material,excipient, lubricant, buffer, antibacterial, bulking agent (such asmannitol), anti-oxidants (ascorbic acid of sodium bisulfite) or thelike.

The dose administered must be carefully adjusted according to age,weight and condition of the patient, as well as the route ofadministration, dosage form and regimen and the desired result.

The pharmaceutical compositions of the disclosure may be administered inthe dosage forms in single or divided doses of one to four times daily.It may be advisable to start a patient on a low dose combination andwork up gradually to a high dose combination.

Tablets of various sizes can be prepared, e.g., of about 1 to 2000 mg intotal weight, containing one or both of the active pharmaceuticalingredients, with the remainder being a physiologically acceptablecarrier of other materials according to accepted pharmaceuticalpractice. These tablets can be scored to provide for fractional doses.Gelatin capsules can be similarly formulated.

Liquid formulations can also be prepared by dissolving or suspending oneor the combination of active substances in a conventional liquid vehicleacceptable for pharmaceutical administration so as to provide thedesired dosage in one to four teaspoonful.

Dosage forms can be administered to the patient on a regimen of, forexample, one, two, three, four, five, six, or other doses per day

In order to more finely regulate the dosage schedule, the activesubstances may be administered separately in individual dosage units atthe same time or carefully coordinated times. Since blood levels arebuilt up and maintained by a regulated schedule of administration, thesame result is achieved by the simultaneous presence of the twosubstances. The respective substances can be individually formulated inseparate unit dosage forms in a manner similar to that described above.

In formulating the compositions, the active substances, in the amountsdescribed above, may be compounded according to accepted pharmaceuticalpractice with a physiologically acceptable vehicle, carrier, excipient,binder, preservative, stabilizer, flavor, etc., in the particular typeof unit dosage form.

Illustrative of the adjuvants which may be incorporated in tablets arethe following: a binder such as gum tragacanth, acacia, corn starch orgelatin; an excipient such as dicalcium phosphate or cellulose; adisintegrating agent such as corn starch, potato starch, alginic acid orthe like; a lubricant such as stearic acid or magnesium stearate; asweetening agent such as sucrose, aspartame, lactose or saccharin; aflavoring agent such as orange, peppermint, oil of wintergreen orcherry. When the dosage unit form is a capsule, it may contain inaddition to materials of the above type a liquid carrier such as a fattyoil. Various other materials may be present as coatings or to otherwisemodify the physical form of the dosage unit. For instance, tablets orcapsules may be coated with shellac, sugar or both. A syrup of elixirmay contain the active compound, water, alcohol or the like as thecarrier, glycerol as solubilizer, sucrose as sweetening agent, methyland propyl parabens as preservatives, a dye and a flavoring such ascherry or orange.

One embodiment of this disclosure includes methods of treating,preventing, or diagnosing a particular disease or condition byadministering the disclosed nanoparticles, composite nanoparticles,nanosuspension, or nanocapsules to a subject. In many instances, thenanoparticles, composite nanoparticles, or nanocapsules are administeredalone or can be included within a pharmaceutical composition. Aneffective amount of a pharmaceutical composition, generally, is definedas that amount sufficient to ameliorate, reduce, minimize, or limit theextent of the disease or condition. More rigorous definitions may apply,including elimination, eradication, or cure of the disease or condition.

“Nanoparticles” are solid particles of an average particle diameter of,for example, less than about 1 micron (micrometer). One micron is 1,000nanometers (nm). “Stabilized” nanoparticles are nanoparticles coatedwith a stabilizing material and having a reduced tendency foraggregation and loss of dispersion with respect to nanoparticles of thecompound of the disclosure without a stabilizing coating. A nano-sprayis a spray containing nanoparticles or a spray that producesnanoparticles. A nanodispersion is a dispersion containingnanoparticles. A nanosuspension is a suspension containingnanoparticles.

The liquid formulations useful herein may comprise a solvent, solution,suspension, microsuspension, nanosuspension, emulsion, microemulsion,gel or even a melt containing the active component or components. Insome embodiments the nanoparticles, nanofibers, or nanofibrils may be inthe form of, or within or on, granules, powders, suspensions, solutions,dissolvable films, mats, webs, tablets, or releasable forms particularlyreleasable dosage forms. Other particular useful forms are concentratesto which a diluting liquid is added prior to use. The product may alsobe sprayed onto the inner surface of a container to which a liquid isadded later prior to use and the nanoparticles, nanofibers, ornanofibrils, are released into the liquid. Pharmaceutical compositionsof the present disclosure can include nanoparticles, compositenanoparticles, nanosuspension, or nanocapsules of the presentdisclosure.

The composition may also include various antioxidants to retardoxidation of one or more active ingredient or nanoparticles, compositenanoparticles, nanosuspension, or nanocapsules. The prevention of theaction of microorganisms can be brought about by preservatives such asvarious antibacterial and antifungal agents, including but not limitedto parabens (e.g., methylparabens, propylparabens), chlorobutanol,phenol, sorbic acid, thimerosal or combinations thereof.

In order to increase the effectiveness of a treatment with thenanoparticles, nanogels, composite nanoparticles, nanosuspension, ornanocapsules of the present disclosure, it may be desirable to combinethese nanoparticles, composite nanoparticles, or nanocapsules with othertherapies effective in the treatment of a particular disease orcondition.

The formulations as described above may be administered for a prolongedperiod, that is, for as long as the potential for a disease or conditionremains or the symptoms continue.

Neurological Symptoms

Mycophenolic Acid and Zika Neurological Disease

The disclosure provides that mycophenolic acid and the otherpharmaceutical compositions and methods of the disclosure will prevent,mitigate, and treat neurological disease resulting from infection byZika virus.

Neurological sequelae of Zika infection include: Guillain Bane Syndome,encephalitis, myelitis, encephalomyelitis, meningitis,meningoencephalitis, facial paralysis, confusion, weakness, cognitivedysfunction and other neurological disorders (Araujo et al., 2016). Manyof these neurological complications are believed to be due to autoimmuneresponses to the viral infection which lead to immunological cells ofthe human body attacking nerves and supporting cells. Mycophenolate is arather unique antiviral drug in that at high doses it has clinicallyimpressive immunosuppressive properties. It has been discovered that byproviding doses of mycophenolic acid that are above the minimum doserequired for its antiviral effect but generally below the high dosesused clinically for prevention of transplantation rejection, thatneurological sequelae of Zika virus infection can be prevented,mitigated, and treated.

Mycophenolic Acid and Neurological Diseases Due to Other Viruses

In addition to Zika, other viruses are well known to have neurologicalsequellae, including West Nile virus (Money et al., 2013), influenzavirus (Cardenas et al., 2014, norovirus (Chen et al., 2009), denguevirus (Sil et al., 2017), and other flaviviridae (Soloman et al., 2016).The disclosure provides for the use of mycophenolic acid which canprevent and treat neurological sequelae of other viruses including theabove.

Money et al., 2013, reviewed mouse and hamster models for neurologicalsequelae of West Nile virus and showed how the animal models compare tothe human neurological sequelae. The mouse model is utilized todemonstrate that administration of mycophenolic acid after infectionwith West Nile virus prevents and treats a range of neurologicaldiseases and symptoms caused by West Nile virus.

The disclosure provides for the use of mycophenolic acid in preventingand treating neurological sequelae of viral diseases is enhanced bysimultaneously administering a low nucleotide diet, and especially alow-guanosine diet. Limiting the availability of guanosine from the dietreduces the body pool of guanosine, thus enhancing the guanosinelowering effect of mycophenolic acid, which is responsible for itsantiviral and anti-inflammatory and immunosuppressive properties.

In addition, the disclosure provides a method of preventing and/ortreating postviral neurological syndromes in a patient, the methodcomprising the steps of: selecting a patient in need of preventingand/or treating postviral neurological syndrome; administering to thepatient at least one agent selected from the group consisting ofminocycline, doxycycline, tetracycline, tetracycline derivatives,L-DOPA, dopamine, and combinations thereof; wherein the postviraslneurological syndrome is prevented and/or treated in the patient. Thedisclosure provides a method wherein the postviral neurologicalsyndromes is as a result of infection by a virus selected from the groupconsisting of Zika virus, Norovirus, Respiratory Syncytial Virus,Influenza, Adenovirus 5, HPV 11, Lassa Fever virus, Powassan virus, RiftValley virus, and combinations thereof. The disclosure provides a methodwherein at least one agent is administered in topical form. Araujo, A.Q., Silva, M. T., Araujo, A. P. (2016). Zika virus-associatedneurological disorders: a review. Brain 139: 2122-2130. Cárdenas, G.,Soto-Hernández, J. L., Díaz-Alba, A., Ugalde, Y., Mérida-Puga, J.,Rosetti, M., Sciutto, E. (2014). Neurological events related toinfluenza A (H1N1) pdm09. Influenza Other Respir Viruses 8: 339-346.Chen, S. Y., Tsai, C. N., Lai, M. W., Chen, C. Y., Lin, K. L., Lin, T.Y., Chiu, C. H. (2009). Norovirus infection as a cause ofdiarrhea-associated benign infantile seizures. Clin Infect Dis 48:849-855. Money, J. D., Siddharthan, V., Wang, H. (2013). Neurologicalapproaches for investigating West Nile virus disease and its treatmentin rodents. Antiviral Res 100: 535-545. Sil, A., Biswas, T., Samanta,M., Konar, M. C., De, A. K., Chaudhuri, J. (2017). Neurologicalmanifestations in children with dengue fever: an Indian perspective.Trop Doct 47: 145-149. Soloman T. (2016). Flavivirus encephalitis andother neurological syndromes (Japanese encephalitis, WNV, Tick borneencephalits, Dengue, Zika virus. International Journal of InfectiousDiseases 45S: -24.

Packaging/Treatment Kits

The present disclosure relates to a kit for conveniently and effectivelycarrying out the methods in accordance with the present disclosure. Suchkits may be suited for the delivery of solid oral forms such as tabletsor capsules. Such a kit may include a number of unit dosages. Such kitscan include a means for containing the dosages oriented in the order oftheir intended use. An example of a means for containing the dosages inthe order of their intended uses is a card. An example of such a kit isa “blister pack”. Blister packs are well known in the packaging industryand are widely used for packaging pharmaceutical unit dosage forms. Ifdesired, the blister can be in the form of a childproof blister, i.e., ablister that is difficult for a child to open, yet can be readily openedby an adult. If desired, a memory aid can be provided, for example inthe form of numbers, letters, or other markings or with a calendarfeature and/or calendar insert, designating the days and the sections ofa day in the treatment schedule in which the dosages can beadministered, such as an AM dose is packaged with a “mid day” and a PMdose.; or an AM dose is packaged with a PM dose. Alternatively, placebodosages, or vitamin or dietary supplements, either in a form similar toor distinct from the pharmaceutical active dosages, can be included.

Blister packs, clamshells or trays are forms of packaging used forgoods; thus, the disclosure provides for blister packs, clamshells ortrays comprising a composition (e.g., a (the multi-ingredientcombination of drugs of the disclosure) combination of activeingredients) of the disclosure. Blister packs, clamshells or trays canbe designed to be non-reclosable, so consumers can tell if a package hasalready opened. They are used to package for sale goods where producttampering is a consideration, such as the pharmaceuticals of thedisclosure. In one aspect, a blister pack of the disclosure comprises amoulded PVC base, with raised areas (the “blisters”) to contain thetablets, pills, etc. comprising the combinations of the disclosure,covered by a foil laminate. Tablets, pills, etc. are removed from thepack either by peeling the foil back or by pushing the blister to forcethe tablet to break the foil. In one aspect, a specialized form of ablister pack is a strip pack.

In one aspect, a blister pack also comprises a method of packaging wherethe compositions comprising combinations of ingredients of thedisclosure are contained in-between a card and a clear PVC. The PVC canbe transparent so the item (pill, tablet, geltab, etc.) can be seen andexamined easily; and in one aspect, can be vacuum-formed around a mouldso it can contain the item snugly and have room to be opened uponpurchase. In one aspect, the card is brightly colored and designeddepending on the item (pill, tablet, geltab, etc.) inside, and the PVCis affixed to the card using pre-formed tabs where the adhesive isplaced. The adhesive can be strong enough so that the pack may hang on apeg, but weak enough so that this way one can tear open the join andaccess the item. Sometimes with large items or multiple enclosed pills,tablets, geltabs, etc., the card has a perforated window for access. Inone aspect, more secure blister packs, e.g., for items such as pills,tablets, geltabs, etc. of the disclosure are used, and they can compriseof two vacuum-formed PVC sheets meshed together at the edges, with theinformative card inside.

In one aspect, blister packaging comprises at least two components(e.g., is a multi-ingredient combination of drugs of the disclosure): athermoformed “blister” which houses the product (e.g., a pharmaceuticalcombination of the disclosure), and then a “blister card” that is aprinted card with an adhesive coating on the front surface. During theassembly process, the blister component, which is most commonly made outof PVC, is attached to the blister card using a blister machine. Thismachine introduces heat to the flange area of the blister whichactivates the glue on the card in that specific area and ultimatelysecures the PVG blister to the printed blister card. The thermoformedPVG blister and the printed blister card can be as small or large.

As discussed herein, the products of manufacture of the disclosure cancomprise the packaging of the therapeutic drug combinations of thedisclosure, alone or in combination, as “blister packages” or as aplurality of packettes, including as lidded blister packages, liddedblister or blister card or packets, or a shrink wrap.

Other means for containing said unit dosages can include bottles andvials, wherein the bottle or vial comprises a memory aid, such as aprinted label for administering said unit dosage or dosages. The labelcan also contain removable reminder stickers for placement on a calendaror dayminder to further help the patient to remember when to take adosage or when a dosage has been taken.

Topical Formulations

The term “topical” as employed herein relates to the use of a compound,derivative or analogue as described herein, incorporated in a suitablepharmaceutical carrier, and applied at the site for exertion of localaction. Accordingly, such topical compositions including those forms inwhich the compound is applied externally by direct contact with the skinsurface to be treated. Conventional forms for this purpose includeointments, liniments, creams, shampoos, lotions, pastes, jellies,sprays, aerosols, soaps, and the like, and may be applied in patches orimpregnated dressings depending on the part of the body to be treated.The term “ointment” embraces formulations (including creams) havingoleaginous, absorption, water-soluble and emulsion-type bases, e.g.,petrolatum, lanolin, polyethylene glycols, as well as mixtures of these.

For topical use, the agent of the disclosure can be advantageouslyformulated using ointments, creams, liniments or patches as a carrier ofthe active ingredients. Also, these formulations may or may not containpreservatives, depending on the dispenser and nature of use. Suchpreservatives include those mentioned above, and methyl-, propyl-, orbutyl-parahydroxybenzoic acid, betain, chlorhexidine, benzalkoniumchloride, and the like. Various matrices for slow release delivery mayalso be used. Typically, the dose to be applied is in the range of about0.1 ng to about 100 mg per day, or about 1 ng to about 10 mg per day, orabout 10 ng to about 1 mg per day depending on the formulation.Non-limiting examples of topical products can include, withoutlimitation, application stick, mascara, eyebrow coloring products, eyeshadow or other eye lid coloring products, eyeliner, make-up removalproducts, antiaging products, facial or body powder, nail polish,mousse, sprays, styling gels, nail conditioner, bath and shower gels,shampoos, conditioners, cream rinses, hair dyes and coloring products,hair conditioners, sun tanning lotions and creams and sprays, sunscreensand sunblocks, skin conditioners, cold creams, moisturizers, hairsprays, soaps, body scrubs, exfoliants, astringents, depilatories andpermanent waving solutions, antidandruff formulations, antisweat andantiperspirant compositions, shaving, preshaving and after shavingproducts, moisturizers, deodorants, cold creams, cleansers, skin gels,and rinses.

Furthermore, the topical product can be applied topically through theuse of a patch or other delivery device. Delivery devices can include,but are not limited to, those that can be heated or cooled, as well asthose that utilize iontophoresis or ultrasound.

For instance, the topical product can be applied, for example, byapplying a composition in the form of a skin lotion, clear lotion, milkylotion, cream, gel, foam, ointment, paste, emulsion, spray, conditioner,tonic, cosmetic, application stick, pencil, foundation, nail polish,after-shave, or the like which is intended to be left on the skin orother keratinous tissue (i.e., a “leave-on” composition). After applyingthe composition to the keratinous tissue (e.g., skin), it in oneembodiment, it is left on for a period of at least about 15 minutes, orat least about 30 minutes, or at least about 1 hour, or for at leastseveral hours, e.g., up to about 12 hours. In one embodiment, thetopical product is left on overnight. In another embodiment, the topicalproduct is left on all day. Any part of the external portion of theface, hair, and/or nails can be treated, (e.g., face, lips, under-eyearea, eyelids, scalp, neck, torso, arms, legs, chest, hands, legs, feet,fingernails, toenails, scalp hair, eyelashes, eyebrows, etc.).

Any suitable method can be used to apply the topical product, includingbut not limited to for example using the palms of the hands and/orfingers or a device or implement (e.g., a cotton ball, swab, pad,applicator pen, spray applicator, eyebrow brush, eyebrow brush pencil,pencil, mascara brush, etc.) Another approach to ensure a continuousexposure of the keratinous tissue to at least a minimum level of thetopical product is to apply the compound by use of a patch applied,e.g., to the face. The patch can be occlusive, semi-occlusive ornon-occlusive, and can be adhesive or non-adhesive. The topical productcan be contained within the patch or be applied to the skin prior toapplication of the patch. The patch can also include additional activessuch as chemical initiators for exothermic reactions. The patch can beleft on for any suitable period of time. For example, a period of atleast about 5 minutes, or at least about 15 minutes, or at least about30 minutes, or at least about 1 hour, or at night as a form of nighttherapy, or in another embodiment all day.

Administration

The pharmaceutical compositions may be optimized for particular types ofdelivery. For example, pharmaceutical compositions for oral delivery areformulated using pharmaceutically acceptable carriers that are wellknown in the art. The carriers enable the agents in the composition tobe formulated, for example, as a tablet, pill, capsule, solution,suspension, sustained release formulation; powder, liquid or gel fororal ingestion by the subject.

The liquid or solid compositions may contain suitable pharmaceuticallyacceptable excipients as set out above. Preferably the compositions areadministered by the oral, intranasal or respiratory route for local orsystemic effect. Compositions in preferably sterile pharmaceuticallyacceptable solvents may be nebulized by use of inert gases. Nebulizedsolutions may be breathed directly from the nebulizing device or thenebulizing device may be attached to a face mask, tent or intermittentpositive pressure breathing machine. Solution, suspension or powdercompositions may be administered, preferably orally or nasally, fromdevices that deliver the formulation in an appropriate manner.

Typically, the composition may be applied repeatedly for a sustainedperiod of time topically on the part of the body to be treated, forexample, the eyelids, eyebrows, skin or scalp. The dosage regimen willgenerally involve regular, such as daily, administration for a period oftreatment of at least one month, or at least three months, or at leastsix months.

Alternatively, the composition may be applied intermittently, or in apulsed manner. Accordingly, an alternative embodiment of the disclosureis to apply the composition on an intermittent or pulsed dosageschedule. For example, the composition of the disclosure may be used fortwo or more days, stopped, then restarted again at a time from between 2weeks to 3 months later, and at even more long-spaced intervals in thecase of the scalp.

The treatments may include various “unit doses.” Unit dose is defined ascontaining a predetermined-quantity of the therapeutic composition. Thequantity to be administered, and the particular route and formulation,are within the skill of those in the clinical arts. A unit dose need notbe administered as a single injection but may comprise continuousinfusion over a set period of time. Alternatively, the amount specifiedmay be the amount administered as the average daily, average weekly, oraverage monthly dose.

The disclosure will be illustrated in more detail with reference to thefollowing Examples, but it should be understood that the presentdisclosure is not deemed to be limited thereto.

EXAMPLES Example 1 Prevention and Treatment of a Male at Risk for ZikaInfection

In this example, the new method prevents or minimizes infection ofhumans by Zika virus. Here, a male at risk for being stung by an Aedesmosquito takes the following steps. He starts taking daily low dose oralmycophenolate one week before he travels to a Zika infested area andcontinues taking it while in the area. He applies a melanin containinglotion daily to skin not covered by clothing.

The use of these methods inhibits the infection in the following ways.

1. The lotion containing melanin is applied to the skin and is partiallyabsorbed into the epidermis and dermis. It rapidly evaporates to leave athin tough film. The external film of melanin minimizes or entirelyprevents the entry of the virus in the skin from the stinger of theAedes mosquito vector. If any virus is successfully injected into theepidermis or dermis, the absorbed melanin, which is toxic to the virusbut not to human cells, eliminates or reduces the amount of live viruswhich has been introduced.

2. It has been demonstrated that three types of cells in the skin arenormally susceptible to infection by the Zika virus: epidermalkeratinocytes, dermal fibroblasts, and (dermal) macrophages. It has alsobeen demonstrated that mycophenolate dramatically reduces guanosinelevels in all three cell types. Thus because of relative depletion ofguanosine in these cells, there is reduced (or absent) replication ofthe viral RNA in these cells as the guanosine necessary for replicationof RNA is in short supply. Thus viral particles injected are only ableto reproduce at a lower amount, or not at all, minimizing or terminatingthe infective load.

3. If in spite of the prior steps, the virus is successful inpenetrating to the blood stream and causing a viremia, the systemicmycophenolate directly inhibits the the replication of the Zika virus inthe blood and throughout the body.

4. Note that since a very small amount of antigen is known to triggerthe immune system responses, it is likely that even if the injectedviral load is partially destroyed and the ability of remaining virusparticles to replicate is limited, there is likely to be adequate viralantigen to stimulate the normal antiviral responses of the innate andadaptive immune systems.

Example 2 Prevention and Treatment of a Female at Risk for Pregnancy andZika Infection.

Here, a female who is sexually active and may become pregnant is at riskfor being stung by an Aedes mosquito and takes the following steps. Shestarts on a reduced guanosine diet designed for women who are pregnantor may become pregnant, one week before she travels to a Zika infestedarea and continues adhering to this diet while in the area. She appliesa melanin containing lotion daily to skin not covered by clothing.

1. The lotion containing melanin is applied to the skin and is partiallyabsorbed into the epidermis and dermis. It rapidly evaporates to leave athin tough film. The external film of melanin minimizes or entirelyprevents the entry of the virus in the skin from the stinger of theAedes mosquito vector. If any virus is successfully injected into theepidermis or dermis, the absorbed melanin, which is toxic to the virusbut not to human cells, eliminates or reduces the amount of live viruswhich has been introduced.

2. It has been demonstrated that three types of cells in the skin arenormally susceptible to infection by the Zika virus: epidermalkeratinocytes, dermal fibroblasts, and (dermal) macrophages. The reducedguanosine diet reduces guanosine levels in all three cell types. Thusbecause of relative depletion of guanosine in these cells, there isreduced (or absent) replication of the viral RNA in these cells as theguanosine necessary for replication of RNA is in short supply. Thusviral particles injected are only able to reproduce at a lower amount,or not at all, minimizing or terminating the infective load.

3. If in spite of the prior steps, the virus is successful inpenetrating to the blood stream and causing a viremia, the relative lackof guanosine caused by the reduced diet limits the ability of the virusto replicate.

4. The above steps are successful in interdicting the infectionsufficiently that an embryo or fetus is not damaged by the maternalviral infection.

Example 3

Treatment of a Patient with Multi-Drug Resistant Tuberculosis.

A traveler from the US contracts multi-drug resistant tuberculosis whilein India. There are no known effective antibiotics. The patient isadministered 3 ounces (about 90 gm) of cuttlefish ink (which containsmelanin) mixed in his regular food twice per day for two weeks. Thenmycophenolate mofetil 250 mg twice per day is added. The regimen iscontinued for 3 months leading to cure of the multidrug-resistanttuberculosis.

Example 4

Treatment of a Patient with Infectious Pulmonary Aspergillosis.

As asthma patient contracts infectious pulmonary aspergillosis, a fungaldisease. The patient is administered 2 grams of melanin (1 gm/capsule)mixed in his regular food twice per day for two weeks. Thenmycophenolate mofetil 250 mg twice per day is added. The regimen iscontinued for 3 months leading to cure of the aspergillosis.

Example 5

Diets with Reduced Guanosine Content

These invented diets are low in nucleic acids and their components butare not nucleotide-free. The diets contain approximately 3% to 50% ofthe amount by weight of nucleotides seen in the normal western diet(2000 mg/day, from Ekelman, K. Disodium 5′Guanylate and Disodium5′-Inosate. WHO Food Additives Series, No. 32 (1993), and preferably10%-40%.

The inventor has conducted extensive analysis of the nucleotide contentof human foods from a variety of sources, and evaluated the nutritionalcontent and palatability of potential nucleotide-free diets. Theinventor has concluded that it is not practical for most people to stayon a nucleotide-free diet in a compliant manner for the period of monthsrequired to obtain substantial clinical benefit from this approach. Anucleotide-free diet is unlikely to be sufficiently palatable forextended use and would deter compliance. Also, use of a nucleotide-freediet for months in humans would likely lead to other dietarydeficiencies.

As set forth above, the disclosure provides treatment of a patient witha diet which contains approximately 3% to 50% of the amount by weight ofnucleotides seen in the normal western diet, which contains about 2000mg/day of nucleotides. In exemplary embodiments, the diet of thedisclosure contains a nucleotide content of about 1000 mg/day, of about750 mg/day, of about 500 mg/day, of about 250 mg/day, of about 100mg/day, of about 75 mg/day, of about 50 mg/day, of about 25 mg/day. Inexemplary embodiments, the diet of the disclosure contains a nucleotidecontent compared to the normal Western diet of about 50%, of about 40%,of about 30%, of about 20%, of about 10%, of about 5%, of about 3%. Inexemplary embodiments, the diet of the disclosure contains a nucleotidecontent compared to the normal Western diet of 3-50%, of about 10-40%,of about 20-30%, of about 3-40%, of about 3-30%, of about 10-30%, ofabout 10-20%.

Example 6

Diets with Reduced Guanosine Content Optimized for Women Who arePregnant or May Become Pregnant.

The diets in Example 5 are modified to make them appropriate for womenwho are pregnant. The modified diets contain additional calcium, traceminerals, and B vitamin supplements. A supplement like Ensure or Boostwould be added to the diet. There would be additional fatty acids andprotein.

Example 7 In Vitro Demonstration of Method Efficacy

Using methods similar to those of Diamond et al, 2002, (Diamond, M.,Zachariah, M, and Harris, E. “Mycophenolic Acid Inhibits Dengue VirusInfection by Preventing Replication of Viral RNA.” Virology 304, no. 2(2002): 211-221) mycophenolate and melanin are shown together, or whenadministered sequentially, to inhibit the replication of the Zika virusin vitro. For example, Zika virus is added to monolayers of hepatomacells or hamster kidney cells at several different doses. They areincubated for 2 hours at a temperature of 37 C. The cells are washedseveral times. Mycophenolate or melanin or both are added to the cellsafter they are exposed to Zika. After 72 hours the cells are harvested.RNA, viral antigen, and virion are quantitated. The results show thatmycophenolate and melanin together inhibit almost all replication of theZika virus. Depending on the type of cells used, the dose of Zika virus,the doses of mycophenolate and/or melanin, the viral replication isinhibited in various degrees.

Example 8 Zika

Three in vitro tests showed MPA to be active against Zika Virus. Theprimary screening test (Zika-A) was carried out in monkey Vero cells.The two secondary screening tests were carried out against monkey Verocells (Zika-B) and human cells (Zika-C).

Virus Screened: Zika Virus Virus Strain: MR766 Cell Line: Vero 76Vehicle: DMSO Drug Conc. Range: 0.1-100 μg/ml Control Conc. Range:0.1-100 μg/ml Experiment Number: Zika-089 Control Drug Control AssayControl Assay Name Order Name EC₅₀ EC₉₀ CC₅₀ SI₅₀ SI₉₀ 6-AzauridinePrimary Visual (Cytopathic 0.32 >100 >310 effect/Toxicity) 6-AzauridinePrimary Neutral Red (Cytopathic 0.35 83.3 238 effect/Toxicity) Date DrugDrug Received Compound Assay Assay ARB No. m/dd/yy Name/ID Order NameEC₅₀ EC₉₀ CC₅₀ SI₅₀ SI₉₀ 16-000406 6/18/2016 EP1601 Primary Visual<0.1 >100 >1000 (Cytopathic effect/Toxicity) 16-000406 6/18/2016 EP1601Primary Neutral Red 0.15 14 93 (Cytopathic effect/Toxicity) VirusScreened: Zika virus Virus Strain: MR766 Cell Line: Vero 76 Vehicle:DMSO Drug Conc. Range: 0.1-100 μg/ml Control Conc. Range: 0.1-100 μg/mlExperiment Number: Zika-094 Control Drug Control Assay Control AssayName Order Name EC₅₀ EC₉₀ CC₅₀ SI₅₀ SI₉₀ 6-Azauridine Secondary Visual(Virus yield 1.3 9.9 7.6 reduction)/Neutral Red (Toxicity) 6-AzauridineSecondary Neutral Red (Cytopathic 0.37 9.9 27 effect/Toxicity) Date DrugDrug Received Compound Assay Assay ARB No. m/dd/yy Name/ID Order NameEC₅₀ EC₉₀ CC₅₀ SI₅₀ SI₉₀ 16-000406 7/08/2016 EP1601 Secondary Visual(Virus yield 0.3 2.3 7.7 reduction)/Neutral Red (Toxicity) 16-0004067/08/2016 EP1601 Secondary Neutral Red 0.14 2.3 16 (Cytopathiceffect/Toxicity) Virus Screened: Zika virus Virus Strain: MR766 CellLine: Huh7 Vehicle: DMSO Drug Conc. Range: 0.1-100 μg/ml Control Conc.Range: 0.1-100 μg/ml Experiment Number: Zika-094 Control Drug ControlAssay Control Assay Name Order Name EC₅₀ EC₉₀ CC₅₀ SI₅₀ SI₉₀6-Azauridine Secondary Visual (Virus yield 27.4 >100 >3.6reduction)/Neutral Red (Toxicity) 6-Azauridine Secondary Neutral Red(Cytopathic 1.2 >100 >83 effect/Toxicity) Date Drug Drug ReceivedCompound Assay Assay ARB No. m/dd/yy Name/ID Order Name EC₅₀ EC₉₀ CC₅₀SI₅₀ SI₉₀ 16-000406 7/09/2016 EP1601 Secondary Visual (Virus yield 0.0881.6 18 reduction)/Neutral Red (Toxicity) 16-000406 7/09/2016 EP1601Secondary Neutral Red 0.14 1.6 33 (Cytopathic effect/Toxicity)

Zika Prevention

MPA was pre-incubated with Huh7 cells 4 hours prior to Zika infection.

Virus Screened: Zika virus Virus Strain: MR766 Cell Line: Huh7 Vehicle:DMSO Drug Conc. Range: 0.032-100 μg/ml Control Conc. Range: 0.032-100μg/ml Experiment Number: Zika-138 Control Drug Control Assay ControlAssay Name Order Name EC₅₀ EC₉₀ CC₅₀ SI₅₀ SI₉₀ NITD008 Secondary Visual(Virus yield 0.61 >100 >164 reduction)/Neutral Red (Toxicity) NITD008Secondary Neutral Red (Cytopathic 1.1 >100 >91 effect/Toxicity) DateDrug Drug Received Compound Assay Assay ARB No. m/dd/yy Name/ID OrderName EC₅₀ EC₉₀ CC₅₀ SI₅₀ SI₉₀ 16-000406 11/2/2016 EP1601 SecondaryVisual (Virus yield 42.71 >100 >2.3 reduction)/Neutral Red (Toxicity)16-000406 11/2/2016 EP1601 Secondary Neutral Red 0.17 >100 >590(Cytopathic effect/Toxicity)

MPA was pre-incubated with Huh7 cells 24 hours prior to Zika infection.

Virus Screened: Zika virus Virus Strain: MR766 Cell Line: Huh7 Vehicle:DMSO Drug Conc. Range: 0.032-100 μg/ml Control Conc. Range: 0.032-100μg/ml Experiment Number: Zika-138 Control Drug Control Assay ControlAssay Name Order Name EC₅₀ EC₉₀ CC₅₀ SI₅₀ SI₉₀ NITD008 Secondary Visual(Virus yield 1.0 27 27 reduction)/Neutral Red (Toxicity) NITD008Secondary Neutral Red (Cytopathic 0.77 27 34 effect/Toxicity) Date DrugDrug Received Compound Assay Assay ARB No. m/dd/yy Name/ID Order NameEC₅₀ EC₉₀ CC₅₀ SI₅₀ SI₉₀ 16-000406 6/18/2016 EP1601 Secondary Visual(Virus yield 0.78 1.4 1.8 reduction)/Neutral Red (Toxicity) 16-0004066/18/2016 EP1601 Secondary Neutral Red 0.55 1.4 2.5 (Cytopathiceffect/Toxicity)

MPA was pre-incubated with Vero 76 cells 4 hours prior to Zikainfection.

Virus Screened: Zika virus Virus Strain: MR766 Cell Line: Vero 76Vehicle: DMSO Drug Conc. Range: 0.032-100 μg/ml Control Conc. Range:0.032-100 μg/ml Experiment Number: Zika-138 Control Drug Control AssayControl Assay Name Order Name EC₅₀ EC₉₀ CC₅₀ SI₅₀ SI₉₀ NITD008 SecondaryVisual (Virus yield 7.81 >100 >12.8 reduction)/Neutral Red (Toxicity)NITD008 Secondary Neutral Red (Cytopathic 8.3 >100 0 effect/Toxicity)Date Drug Drug Received Compound Assay Assay ARB No. m/dd/yy Name/IDOrder Name EC₅₀ EC₉₀ CC₅₀ SI₅₀ SI₉₀ 16-000406 11/1/2016 EP1601 SecondaryVisual (Virus yield 17.8 >100 >5.6 reduction)/Neutral Red (Toxicity)16-000406 11/1/2016 EP1601 Secondary Neutral Red >100 >100 0 (Cytopathiceffect/Toxicity)

MPA was pre-incubated with Vero 76 cells 24 hours prior to Zikainfection.

Virus Screened: Zika virus Virus Strain: MR766 Cell Line: Vero 76Vehicle: DMSO Drug Conc. Range: 0.032-100 μg/ml Control Conc. Range:0.032-100 μg/ml Experiment Number: Zika-138 Control Drug Control AssayControl Assay Name Order Name EC₅₀ EC₉₀ CC₅₀ SI₅₀ SI₉₀ NITD008 SecondaryVisual (Virus yield 31.62 >100 >3.2 reduction)/Neutral Red (Toxicity)NITD008 Secondary Neutral Red (Cytopathic 5.1 >100 >20 effect/Toxicity)Date Drug Drug Received Compound Assay Assay ARB No. m/dd/yy Name/IDOrder Name EC₅₀ EC₉₀ CC₅₀ SI₅₀ SI₉₀ 16-000406 11/3/2016 EP1601 SecondaryVisual (Virus yield 10 37 3.7 reduction)/Neutral Red (Toxicity)16-000406 11/3/2016 EP1601 Secondary Neutral Red 8 37 4.6 (Cytopathiceffect/Toxicity)

Example 9 Norovirus

Three in vitro tests showed MPA to be active against Norovirus. Theprimary screening test (NOV-A) was carried out with human norovirus.Additional testing was carried out with mouse norovirus (NOV-B).Secondary testing was done with human norovirus.

Virus Screened: NV Virus Strain: GT₁ Cell Line: HG₂₃ Vehicle: DMSO DrugConc. Range: 0.05-100 uM Control Conc. Range:  3.7-100 uM ExperimentNumber: 16-21 Control Drug Control Assay Control Assay Name Order NameEC₅₀ EC₉₀ CC₅₀ SI₅₀ SI₉₀ 2′C-methyl primary RNA Hybridization 6.617 >300 >45 >18 cytidine (Replicon)/RNA Hybridization (Toxicity) DateDrug Drug Received Compound Assay Assay ARB No. m/dd/yy Name/ID OrderName EC₅₀ EC₉₀ CC₅₀ SI₅₀ SI₉₀ 16-000406 7/19/2016 EP1601 Primary RNAHybridization 0.151 1.3 >100 >622 >77 (Replicon)/RNA Hybridization(Toxicity) Virus Screened: MNV Virus Strain: MNV−₁ Cell Line:RAW_(264.7) Vehicle: DMSO Drug Conc. Range: 0.1-100 uM Control Conc.Range:  1.1-30 uM Experiment Number: 17-09 Control Drug Control AssayControl Assay Name Order Name EC₅₀ EC₉₀ CC₅₀ SI₅₀ SI₉₀ 2′C-methylprimary NR (CPE)/ 1.0 3.2 51 51 16 cytidine NR (Tox) Date Drug DrugReceived Trail Compound Assay Assay ARB No. m/dd/yy No. Name/ID OrderName EC₅₀ EC₉₀ CC₅₀ SI₅₀ SI₉₀ 16-000406 7/19/2016 1 EP1601 Primary NR(CPE)/ 0.123 0.384 32 260 83 NR (Tox) Virus Screened: NV Virus Strain:GT₁ Cell Line: HG₂₃ Vehicle: DMSO Drug Conc. Range: 0.024-100 uM ControlConc. Range:  3.7-100 uM Experiment Number: 17-14 Control Drug ControlAssay Control Assay Name Order Name EC₅₀ EC₉₀ CC₅₀ SI₅₀ SI₉₀ 2′C-methylsecondary qPCR (Replicon)/ 6.0 18 >300 >50 >17 cytidine NR (Tox) DateDrug Drug Received Compound Assay Assay ARB No. m/dd/yy Name/ID OrderName EC₅₀ EC₉₀ CC₅₀ SI₅₀ SI₉₀ 16-000406 7/19/2016 EP1601 Primary qPCR(Replicon)/ 0.219 1.1 64 292 58 NR (Tox)

Example 10 Pandemic Influenza Flu

MPA was highly active against pandemic Influenza A H1N1(California/07/2009).

Virus Screened: Influenza A virus H₁N₁ Virus Strain: California/07/2009Cell Line: MDCK Vehicle: DMSO Drug Conc. Range:  0.1-100 uM ControlConc. Range: 0.32-320 uM Experiment Number: FLU-1195 Control DrugControl Assay Control Assay Name Order Name EC₅₀ EC₉₀ CC₅₀ SI₅₀ SI₉₀Ribavirin Primary Visual (Cytopathic 3.7 >320 >86 effect/Toxicity)Ribavirin Primary Neutral Red (Cytopathic 4.1 >320 >78 effect/Toxicity)Date Drug Drug Received Compound Assay Assay ARB No. m/dd/yy Name/IDOrder Name EC₅₀ EC₉₀ CC₅₀ SI₅₀ SI₉₀ 16-000406 3/01/17 EP1601 PrimaryVisual <0.1 >100 >1000 (Cytopathic effect/Toxicity) 16-000406 3/01/17EP1601 Primary Neutral Red <0.1 >100 >1000 (Cytopathic effect/Toxicity)

Example 11 Respiratory Syncytial Virus

MPA was highly active against Respiratory Syncytial Virus

Virus Screened: Respiratory syncytial virus Virus Strain: A₂ Cell Line:MA⁻¹⁰⁴ Vehicle: DMSO Drug Conc. Range:  0.1-100 μg/ml Control Conc.Range: 0.32-320 μg/ml Experiment Number: RSV⁻⁰²⁶⁸ Control Drug ControlAssay Control Assay Name Order Name EC₅₀ EC₉₀ CC₅₀ SI₅₀ SI₉₀ RibavirinPrimary Visual (Cytopathic 7.6 >320 >42 effect/Toxicity) RibavirinPrimary Neutral Red (Cytopathic 12 >320 >27 effect/Toxicity) Date DrugDrug Received Compound Assay Assay ARB No. m/dd/yy Name/ID Order NameEC₅₀ EC₉₀ CC₅₀ SI₅₀ SI₉₀ 16-000406 3/01/2017 EP1601 Primary Visual<0.1 >100 >1000 (Cytopathic effect/Toxicity) 16-000406 3/01/2017 EP1601Primary Neutral Red <0.1 >100 >1000 (Cytopathic effect/Toxicity)

Example 12 Others

Additionally, MPA was active against the following viruses:

Adenovirus 5, HPV 11, Lassa Fever, Powassan, Rift Valley.

Virus Screened: Adenovirus₅ Virus Strain: Adenoid₇₅ Cell Line: A₅₄₉Vehicle: DMSO Drug Conc. Range: 0.1-100 μg/ml Control Conc. Range:0.1-100 μg/ml Experiment Number: ADV⁻⁰¹⁷² Control Drug Control AssayControl Assay Name Order Name EC₅₀ EC₉₀ CC₅₀ SI₅₀ SI₉₀ 2,3-Dideoxy-Primary Visual (Cytopathic 3.2 >100 >31 cytidine effect/Toxicity)2,3-Dideoxy- Primary Neutral Red (Cytopathic 3.2 >100 >31 cytidineeffect/Toxicity) Date Drug Drug Received Compound Assay Assay ARB No.m/dd/yy Name/ID Order Name EC₅₀ EC₉₀ CC₅₀ SI₅₀ SI₉₀ 16-000406 7/15/2016EP1601 Primary Visual 0.32 15 47 (Cytopathic effect/Toxicity) 16-0004067/15/2016 EP1601 Primary Neutral Red 0.31 12 39 (Cytopathiceffect/Toxicity) Virus Screened: Human papillomavirus₁₁ Virus Strain:RRP₃₃₇₁₅LTR Cell Line: C⁻³³A Vehicle: DMSO Drug Conc. Range: 0.048-150μM Control Conc. Range: 0.048-150 μM Experiment Number: HPV₁₆₋₁₅ ControlDrug Control Assay Control Assay Name Order Name EC₅₀ EC₉₀ CC₅₀ SI₅₀SI₉₀ 9-[2-(phosphono- Primary Nano-Glo Luciferase 7.27 25.21 140.59 19 6methoxy)ethyl]guanine (NanoLuc)/Cell Titer-Glo (Toxicity) Date Drug DrugReceived Compound Assay Assay ARB No. m/dd/yy Name/ID Order Name EC₅₀EC₉₀ CC₅₀ SI₅₀ SI₉₀ 16-000406 7/15/2016 EP1601 Primary Nano-Glo 0.793.67 >150 >191 >41 Luciferase (NanoLuc)/Cell Titer-Glo (Toxicity) VirusScreened: Lassa fever virus Virus Strain: Josiah Cell Line: VeroVehicle: DMSO Drug Conc. Range: 0.1-100 μg/ml Control Conc. Range:0.1-100 μM Experiment Number: LASV⁻⁰¹⁵ Control Drug Control AssayControl Assay Name Order Name EC₅₀ EC₉₀ CC₅₀ SI₅₀ SI₉₀ Ribavirin PrimaryCrystal violet 32 >100 >3.1 (Plaque reduction)/ Neutral red (Toxicity)Date Drug Drug Received Compound Assay Assay ARB No. m/dd/yy Name/IDOrder Name EC₅₀ EC₉₀ CC₅₀ SI₅₀ SI₉₀ 16-000406 7/15/2016 EP1601 PrimaryCrystal violet 0.2 >100 >500 (Plaque reduction)/ Neutral red (Toxicity)Virus Screened: Powassan virus Virus Strain: LB Cell Line: BHK Vehicle:DMSO Drug Conc. Range:    0.1-100 μg/ml Control Conc. Range:0.00001-0.01 μg/ml Experiment Number: POW⁻⁰⁵⁵ Control Drug Control AssayControl Assay Name Order Name EC₅₀ EC₉₀ CC₅₀ SI₅₀ SI₉₀ Infergen PrimaryVisual (Cytopathic 0.00032 >0.01 >31 effect/Toxicity) Infergen PrimaryNeutral Red (Cytopathic 0.00026 >0.01 >38 effect/Toxicity) Date DrugDrug Received Compound Assay Assay ARB No. m/dd/yy Name/ID Order NameEC₅₀ EC₉₀ CC₅₀ SI₅₀ SI₉₀ 16-000406 7/15/2016 EP1601 Primary Visual 0.323.2 10 (Cytopathic effect/Toxicity) 16-000406 7/15/2016 EP1601 PrimaryNeutral Red 0.36 1.1 3.1 (Cytopathic effect/Toxicity) Virus Screened:Rift Valley fever virus Virus Strain: MP⁻¹² Cell Line: Vero₇₆ Vehicle:DMSO Drug Conc. Range: 0.1-100 μg/ml Control Conc. Range:  1-1000 μg/mlExperiment Number: RVFV⁻¹⁵⁴ Control Drug Control Assay Control AssayName Order Name EC₅₀ EC₉₀ CC₅₀ SI₅₀ SI₉₀ Ribavirin Primary Visual(Cytopathic 11 >1000 >91 effect/Toxicity) Ribavirin Primary Neutral Red(Cytopathic 12 1000 >83 effect/Toxicity) Date Drug Drug ReceivedCompound Assay Assay ARB No. m/dd/yy Name/ID Order Name EC₅₀ EC₉₀ CC₅₀SI₅₀ SI₉₀ 16-000406 7/15/2016 EP1601 Primary Visual 3.1 26 8.4(Cytopathic effect/Toxicity) 16-000406 7/15/2016 EP1601 Primary NeutralRed 4 17 4.3 (Cytopathic effect/Toxicity)

Example 13

Below are the Day 7 and 33 results for the test panel in Cuttlefish Ink(Nortindal Sea Products lot N-L:IR:14/14B.B). The material showed goodacross the board reduction of the microbial challenge panel used. Thepanel includes representatives of common Gram negative and Gram positivepathogens and opportunistic pathogens, mold and yeast. The “Controlsample” counts are for the un-spiked product and show it to maintain <10colony-forming units per gram stored at ambient temperature.

Results; 33—day exposure at 20-25 C: (Counts in colony forming units/g)

day 33% reduction of initial Organism [ATCC #] T₀ T_(day 7) T_(day 33)spike S. aureus [6578] 1.58 × 10³ 6.0 × 10² 3.0 × 10¹ 98.1% E. coli[8739] 2.34 × 10³ 6.8 × 10² 1.1 × 10² 95.3% P. aeruginosa [9027] 1.48 ×10³ <10 <10 99.4% C. albicans (yeast)  4.5 × 10² <10 <10 98.0% [10231]A. brasiliensis (mold)  3.3 × 10² 1.2 × 10² 3.0 × 10¹ 90.9% [16404]Central sample: <10

Results; 7—day exposure at 20-25 C (Counts in colony forming units/g)

7-day % reduction of initial Organism [ATCC #] T₀ T_(day 7) spike S.aureus [6578] 1.58 × 10³ 6.0 × 10² 62.0% E. coli [8739] 2.34 × 10³ 6.8 ×10² 70.9% P. aeruginosa [9027] 1.48 × 10³ <10 99.4% C. albicans (yeast)[10231]  4.5 × 10² <10 98.0% A. brasiliensis (mold) [16404]  3.3 × 10²1.2 × 10² 63.6%

Control sample: <10

Example 14 Report of Microbiological Testing Cuttlefish Ink

Log Inoculum Day 1 Day 2 Day 3 Day 7 Reduction Staphylocos Mean 1.08E+061.60E+06 1.67E+06 1.60E+06 5.95E+05 0.3 NA/FIO aureus Count ATCC 6538 %−48.14181 −54.1667  −47.6852  44.9074 reduction Eschericia coli Mean1.20E+06 7.80E+05 3.05E+05 1.94E+05 1.97E+04 1.8 NA/FIO ATCC 8739 Count% 34.7280 74.4770 83.8075 98.3556 reduction Pseudomonas Mean 1.08E+066.50E+05 1.13E+05 3.05E+04 3.10E+03 2.5 NA/FIO aeruginosa Count ATCC9027 % 39.5349 89.5349 96.7442 99.7116 reduction Candida Mean 5.05E+056.45E+05 3.85E+05 1.68E+05 3.95E+02 3.1 NA/FIO albicans Count ATCC 10231% −27.7228  23.7624 67.1287 99.9218 reduction Aspergillus Mean 9.85E+051.16E+06 1.04E+06 1.06E+06 6.95E+05 0.2 NA/FIO brasiliensis Count ATCC16404 % −17.2589  −5.0761 −7.6142 29.4416 reduction

Example 15

Low Guanosine Diet Enhances Efficacy of Oseltamivir in Treating andReducing Mortality from Pandemic Influenza Virus.

The inventor has discovered that low guanosine diets can dramaticallyand surprisingly enhance the efficacy of oseltamivir and otherneuraminidase inhibitors for treatment and prevention of viralinfluenza, including pandemic influenza, and other viruses.

The LD₅₀ and LD₉₀ were determined for Influenza A/Ca/04/2009 (H1N1)virus in adult C57BL/6 mice on a low guanosine diet, and theeffectiveness of oseltamivir was confirmed. Mouse adapted influenzaA/California/04/2009 (H1N1pdm) was amplified in Madin-Darby caninekidney cells. There were initially 10 mice per infection group; however,mice found dead the day of the viral infection were excluded from theresults. Survival was based on body weight loss cutoffs of <30% ofinitial weight. Group A was fed the control diet (Harlan mouse labdiet), and Group B was fed a low guanosine diet, (Purina Mills #5755).Oseltamivir was given to both groups IP, BID for five days beginningfour hours pre-infection. At 21 days post-infection, 4/10 (40%) of themice in Group A (control diet) survived, and 9/9 (100%) of the mice ingroup B (low guanosine diet) survived. This demonstrated that a lowguanosine diet more than doubled the efficacy of oseltamivir inpreventing death from pandemic influenza virus.

Example 16 Prevention and Mitigation of West Nile Virus Disease by a LowGuanosine Diet Administered 0-4 Weeks Before Infection in MiceIntroduction

This experiment demonstrated that feeding a low-nucleotide diet (lowguanosine diet) to mice before infection with West Nile Virusdemonstrated a significant preventive effect on the disease. Reductionof the nucleotide pool available for DNA and RNA synthesis has beendemonstrated to reduce the replication of both microbes and lymphocytes.Nucleotides and their precursors come from two sources—nutrition andcellular synthetic pathways.

The current study uses a series of experimental groups with differenttimes for pre-feeding, which are expected to show a range of effects.This allowed us to study the preventive effects of diet on West NileVirus Disease.

Materials and Methods

Animals: C57BL/6 mice, greater than 7 weeks of age, from Charles RiverLaboratories.

Viruses: WN02 stock (KERN) grown in C6/36 mosquito cells was used. Viralcultures were first confirmed to be mycoplasma-free using the PlasmoTestkit

Diets: Pellet TestDiets™ were obtained from Purina Mills. The lownucleotide diet was #5755 and the control diet was #5008.

Infectious cell culture assay: The virus titer in tissues were assayedusing the virus yield assay where a specific volume of tissue homogenatewas added to the first tube of a series of dilution tubes. Serialdilutions were made and added to Vero cells. Six days later the viralcytopathic effect (CPE) was used to identify the end-point of infection.Four replicates were used to calculate the infectious doses.

Experimental Design

See Table. Adult C57BL/6 female mice were randomized to the groups. Allmice were fed diet with nucleotides (Purina Diet 5008) beginning at 4weeks before viral challenge, except for mice in groups 7 and 2 fed lownucleotide diet (Purina Diet 5755). At 0, −1, and −2 weeks before viralchallenge, diets of mice in groups 1, 3, 5, and 2 were changed tolow-nucleotide diets (Table 1). Overall, the effects of low-nucleotidediet on WNV disease were evaluated when initiated on 0, 1, 2, and 4weeks before viral challenge. The assigned diets were fed until the endon the study 21 days after viral challenge.

Sera collected at day 3 and spleen and kidney tissues at day 6 ingroup-B mice were assayed for WNV infectious titers. Survival, wholebody weight, and disease signs were monitored throughout the experimentto day 21.

TABLE 1 Experimental design. Mice per Infected group Group # WNV, shamCompound Diet initiation 20 1A WNV Diet 5755 low −0 weeks beforenucleotides challenge 10 1B WNV Diet 5755 low −0 weeks beforenucleotides challenge 20 3A WNV Diet 5755 low −1 weeks beforenucleotides challenge 10 3B WNV Diet 5755 low −1 weeks beforenucleotides challenge 20 5A WNV Diet 5755 low −2 weeks beforenucleotides challenge 10 5B WNV Diet 5755 low −2 weeks beforenucleotides challenge 20 7A WNV Diet 5755 low −4 weeks beforenucleotides challenge 10 7B WNV Diet 5755 low −4 weeks beforenucleotides challenge 20 9A WNV Diet 5008 with −4 weeks beforenucleotides challenge 10 9B WNV Diet 5008 with −4 weeks beforenucleotides challenge 5 2   Sham Diet 5755 low −4 weeks beforenucleotides challenge 5 4   Sham Diet 5008 with −4 weeks beforenucleotides challenge

Results and Discussion

To interpret the data, we consider the potential mechanism of action ofa nucleotide-free diet. The hypothesized effect is that virusreplication would be reduced and disease would be less in mice withreduced reserves of nucleotides, because the virus would not have thenucleotides sufficient to fully replicate. The other effect is increasedimmunosuppression in mice with nucleotide-free diets. The outcome ofthese two effects could counteract each other, i.e., there could bereduced viral replication, but increased immunosuppression to allow forincreased viral replication. Additionally, increased immunosuppressioncould reduce neuropathogenesis and disease development.

The mortality of mice fed the low nucleotide diet were statisticallylower (P<0.05) than the mortality of the control diet group, except forthe mortality of mice fed the low nucleotide diet beginning at the timeof infection. Importantly, even the low nucleotide diet administered atthe time of infection appeared to have a lower mortality than thecontrol diet even though it was not statistically lower.

The percentage of mice free of neurological disease appeared to roughlymirror the survival curves. The kidney infectious WNV titers (6 dpi)from mice administered low nucleotide diet at −2, −1, and 0 weeksrelative to viral challenge were statistically lower (P<0.01) using theDunnett's multiple comparison test.

Interestingly, serum and spleen titers from mice administered thenucleotide-free diet at the time of viral challenge were the only titersto be statistically different compare to those of mice administered thecontrol diet. This suggests that the nucleotide pools change veryrapidly in response to diet, even rapidly enough to observe effects whendiet is administered at the time of viral challenge. Perhapsimmunosuppression occurred in mice administered one week or longerbefore viral challenge to elevate viral titers above those of micetreated at the time of viral challenge.

Conclusions

The mortality of mice fed the low nucleotide diet before infection werestatistically lower (P<0.05) than the mortality of the control dietgroup, except for the mortality of mice fed the low nucleotide dietbeginning at the time of infection. This demonstrated the preventiveeffect of the low nucleotide diet on West Nile disease.

Example 17

Prevention and Mitigation of West Nile Virus Disease by a Low GuanosineDiet Administered 2 Days Before Infection in Mice

Introduction

This experiment demonstrated that a low nucleotide diet (low guanosinediet) administered 2 days before infection with West Nile Virus couldprevent and/or mitigate the disease.

Materials and Methods

Animals: C57BL/6 mice, greater than 7 weeks of age, were used (CharlesRiver Laboratories).

Viruses: WN02 stock (KERN) grown in C6/36 mosquito cells dated Oct. 31,2013 was used. Viral cultures were first confirmed to be mycoplasma-freeusing the PlasmoTest kit.

Test articles: Pellet TestDiets™ were obtained from Purina Mills. Thelow nucleotide diet was #5755 and the control diet was #5008. Harlanmouse lab diet routinely fed to mice in this lab was also used as anadditional control.

Infectious cell culture assay: The virus titer in tissues were assayedusing the virus yield assay where a specific volume of tissue homogenatewas added to the first tube of a series of dilution tubes. Serialdilutions were made and added to Vero cells. Six days later the viralcytopathic effect (CPE) was used to identify the end-point of infection.Four replicates were used to calculate the infectious doses.

Experimental Design

Adult C57BL/6 female mice were randomized to the groups (Table 1). Allmice were fed a diet with nucleotides (Purina Diet 5008) beginning at 4weeks before viral challenge, except for groups 13 and 10 that were fedthe Harlan diet used routinely in this lab. At −2 days in relation toviral challenge (designated as day 0), the diets from groups designatedin Table 1 were changed to low nucleotide diet (Groups Sham-6, WNV-9).The assigned diets were fed until the end on the study 21 days afterviral challenge. Survival was monitored throughout the experiment to day21.

TABLE 2 Experimental design. Mice Diet Diet per 5008 5755 Regular groupGroup # WNV Compound dpi dpi diet 15 WNV-9 y low −29 to −3 −2 to 21 —nucleotide diet 15 WNV-11 y diet with −29 to 21 — — nucleotides 15WNV-13 y Harlan — — −29 to 21 regular diet 5 Sham-6 n low −29 to −3 −2to 21 — nucleotide diet 5 Sham-8 n diet with −29 to 21 — — nucleotides 5Sham-10 n Harlan — — −29 to 21 regular diet

Results

The low nucleotide diet administered 2 days before viral challengesignificantly statistically improved survival (P≤0.01) Some reduction inneurological disease signs (paralysis and tremor) was also seen.

Conclusions

A low nucleotide diet administered 2 days before viral challenge,significantly statistically improved survival, preventing in astatistically signicant manner death, the most serious effect of thedisease, and mitigating neurological sequelae of the disease.

Example 18 Experiment Demonstrating Prevention of Zika Virus Infectionby Mycophenolic Acid In Vitro

An experiment was carried out as specified in Example 8. In a ZikaPrevention Trial, MPA was pre-incubated with human cells 4 hours or 24hours before Zika virus infection. In the VYR assays, MPA reduced virusto zero in Huh7 cells pre-incubated with drug for 24 hrs.

The data leading to this assessment is shown in the following table:

TABLE 3 Prevention of Zika virus infection by mycophenolic acid Adminis-tration Cell Time Type Dose w Results MPA μg/ml 100 32 10 3.2 1 0.32 0.1None Virus Titer (Log10 CCID50/0.1 ml) 4 hr pre- Huh7 0.67 4.5 4.5 4.54.5 4.5 4.5 4.5 incubation cells 24 hr pre- Huh7 <.67 <.67 <.67 1.5 3.54.5 4.5 4.5 incubation cells Note: The bolded entries <0.67 represent novirus detected.

It is also important to note that at 4 hours preincubation (seereference to Example 8 above) a large effect of mycophenolic acid(SI₅₀>590) was seen in the Neutral Red assay, and a beneficial effectwas shown in the VYR assay (SI₉₀>2.3).

Conclusion: Mycophenolic acid was shown to completely prevent infectionby Zika virus when given 24 hours before infection, and stronglymitigated the infection when given 4 hours before the infection.

Example 19 Prevention and Mitigation of Pandemic Influenza Infection byMycophenolate Mofetil (Prodrug of Mycophenolic Acid) and a LowNucleotide Diet in Mice Introduction

Reduction of the nucleotide pool available for DNA and RNA synthesis hasbeen demonstrated to decrease the replication of both microbes andlymphocytes. Nucleotides and their precursors come from two sources,nutrition and cellular synthetic pathways. Mycophenolic acid (MPA)inhibits the synthesis of guanosine nucleotides.

We previously titrated the influenza A/Ca/04/2009 (H1N1) virus strain inC57BL/6 mice on a low nucleotide diet, determined the LD50 and LD90, andconfirmed an effective dose of oseltamivir to be used as a positivecontrol. For the current study we evaluated the efficacy of MPA againstthe recently developed mouse model of H1N1 infection in C57BL/6 micemaintained on a low nucleotide diet. Dosing and route was based on thehuman equivalent dose of mycophenolate mofetil (MMF), the prodrug formof MPA that is often used in humans because of its increasedbioavailability. We also evaluated MMF in mice fed a standard diet toestablish the importance of nucleotide restriction in the diet.

Materials and Methods

Animals: Female 18-20 g C57BL/6 mice from Charles River Laboratories(Wilmington, Mass.). Groups of animals were maintained on eitherstandard rodent chow or low nucleotide rodent chow and tap water adlibitum for 7 days prior to virus challenge and continued throughout thestudy.

Virus: Mouse adapted influenza A/California/04/2009 (H1N1pdm). The virusstock was amplified in Madin-Darby canine kidney (MDCK) cells.

Compound: Mycophenolate mofetil (MMF) from Sigma. MMF was prepared in0.5% carboxymethyl cellulose (CMC) for oral administration (PO).Oseltamivir phosphate (hereafter referred to as oseltamivir, which wasused as a positive control) was obtained from Roche (Palo Alto, Calif.)as a powder, and prepared in sterile saline for intraperitoneal (IP)injection.

Experiment design: See Table. Mice were anesthetized by IP injection ofketamine/xylazine followed by intranasal exposure to a 75 μl suspensionof influenza virus. The infectious inoculum of virus was prepared foradministration at dilutions of 1:18,000 and 1:12,000 of the virus stock,corresponding to virus challenge doses of 210 and 320 50% cell cultureinfectious doses (CCID50) used for infection of the low nucleotide dietgroup of mice and the standard diet group respectively. MMF treatmentsand the 0.5% CMC placebo were administered PO twice daily (bid) for 6days. Oseltamivir treatments were given IP bid for 5 days, starting at 4h pre-infection. There were initially 10 mice per infection group,however, 8 mice were found dead the day of the viral infection and wereexcluded from the results (see Table 1). Survival was based on bodyweight loss cutoffs of <30% of initial weight.

Statistical analysis of the data: Survival curves were compared by theMantel-Cox log-rank test. Mean day of death (MDD) comparisons were madeby one-way ANOVA with Dunnett's multiple comparisons test. Differencesin the number of survivors between compound-treated and placebo groupswere analyzed by the Fisher's exact (two-tailed) test. Calculations weremade using Prism 7.0 (GraphPad Software, San Diego, Calif.).

Results

In the present study, we evaluated the efficacy of MMF against aninfluenza A/California/04/2009 (H1N1pdm) infection in C57BL/6 mice fedeither a low nucleotide diet or the standard mouse chow diet for 7 daysprior to virus challenge and continued throughout the study.

1. In the mice fed the standard diet, MMF given at 40 and 4 mg/kg/daysignificantly (P<0.05) increased the Mean Day of Death (MDD) compared tothe placebo-treated animals.

2. In mice fed the low nucleotide diet, treatment with 4 mg/kg/day MMFprovided significant (P<0.05) protection when compared to theplacebo-treated group

Conclusions

The results indicate that C57BL/6 mice fed a low nucleotide diet for 7days prior to challenge with Pandemic Influenza Virus [influenzaA/California/04/2009 (H1N1pdm) strain] had improved survival outcome atthe dose of 4 mg/kg/day MMF bid for 6 days beginning 4 h pre-infection.

While the disclosure has been described in detail and with reference tospecific examples thereof, it will be apparent to one skilled in the artthat various changes and modifications can be made therein withoutdeparting from the spirit and scope thereof.

1. A method of preventing a viral infection in a patient, the methodcomprising the steps of: selecting a patient in need of preventing aviral infection; administering to the patient at least one agent whichdepletes guanosine-containing nucleosides and nucleotides; wherein theviral infection is a flaviviridae virus, and further wherein the viralinfection is prevented in the patient.
 2. The method of claim 1, whereinthe flaviviridae virus is selected from the group consisting ofAbsettarov virus, Alfuy virus Apoi virus Aroa virus, Bagaza virus Borderdisease virus Bouboui virus Bovine diarrhea virus Bussuquara virusBukalasa bat virus, Dengue virus group, Hog cholera virus, Zika virus,Yellow fever virus; Dengue virus; St. Louis encephalitis virus; Japaneseencephalitis virus; Tick-borne encephalitis virus; Omsk hemorrhagicfever virus; Al Khumra virus; Kyasanur Forest disease virus; Louping illvirus; West Nile virus; Kunjin virus; Murray Valley fever virus;Powassan virus; Hepatitis C virus; Hepatitis G virus, and combinationsthereof.
 3. The method of claim 1, wherein the at least one agent whichdepletes guanosine-containing nucleosides and nucleotides is selectedfrom the group consisting of mycophenolate, IMPDH enzyme inhibitors,agents which bind to guanine, or guanosine-containing nucleosides andnucleotides, and combinations thereof.
 4. A method of preventing a viralinfection in a patient, the method comprising the steps of: selecting apatient in need of preventing a viral infection; administering to thepatient a diet which depletes guanosine-containing nucleosides andnucleotides; wherein the viral infection is a flaviviridae virus, andfurther wherein the viral infection is prevented in the patient.
 5. Themethod of claim 4, wherein the flaviviridae virus is selected from thegroup consisting of Absettarov virus, Alfuy virus Apoi virus Aroa virus,Bagaza virus Border disease virus Bouboui virus Bovine diarrhea virusBussuquara virus Bukalasa bat virus, Dengue virus group, Hog choleravirus, Zika virus, Yellow fever virus; Dengue virus; St. Louisencephalitis virus; Japanese encephalitis virus; Tick-borne encephalitisvirus; Omsk hemorrhagic fever virus; Al Khumra virus; Kyasanur Forestdisease virus; Louping ill virus; West Nile virus; Kunjin virus; MurrayValley fever virus; Powassan virus; Hepatitis C virus; Hepatitis Gvirus, and combinations thereof.
 6. The method of claim 4, wherein thediet which depletes guanosine-containing nucleosides and nucleotidescontains a nucleotide content which is selected from the groupconsisting of about 1000 mg/day, of about 750 mg/day, of about 500mg/day, of about 250 mg/day, of about 100 mg/day, of about 75 mg/day, ofabout 50 mg/day, and of about 25 mg/day of nucleotide.
 7. A method ofpreventing a viral infection in a patient, the method comprising thesteps of: selecting a patient in need of preventing a viral infection;administering to the patient at least one agent which depletesguanosine-containing nucleosides and nucleotides; wherein the viralinfection is a respiratory virus, and further wherein the viralinfection is prevented in the patient.
 8. The method of claim 7, whereinthe respiratory virus is selected from the group consisting of Influenzavirus type A, Influenza A H3N2; Influenza A H5N1 (low path); Influenza B(Victoria); Influenza B (Yamagata); Parainfluenza virus-3;Rhinovirus-14; Influenza A H7N9 virus; Influenza A H5N1 (high path),Adenoviruses, Avian influenza, Measles, Parainfluenza virus, Respiratorysyncytial virus (RSV), Rhinoviruses, SARS coronavirus, and combinationsthereof.
 9. The method of claim 7, wherein the at least one agent whichdepletes guanosine-containing nucleosides and nucleotides is selectedfrom the group consisting of mycophenolate, IMPDH enzyme inhibitors,agents which bind to guanine, or guanosine-containing nucleosides andnucleotides, and combinations thereof.
 10. A method of preventing aviral infection in a patient, the method comprising the steps of:selecting a patient in need of preventing a viral infection;administering to the patient a diet which depletes guanosine-containingnucleosides and nucleotides; wherein the viral infection is arespiratory virus, and further wherein the viral infection is preventedin the patient.
 11. The method of claim 10, wherein the respiratoryvirus is selected from the group consisting of Influenza virus type A,Influenza A H3N2; Influenza A H5N1 (low path); Influenza B (Victoria);Influenza B (Yamagata); Parainfluenza virus-3; Rhinovirus-14; InfluenzaA H7N9 virus; Influenza A H5N1 (high path), Adenoviruses, Avianinfluenza, Measles, Parainfluenza virus, Respiratory syncytial virus(RSV), Rhinoviruses, SARS coronavirus, and combinations thereof.
 12. Themethod of claim 10, wherein the diet which depletes guanosine-containingnucleosides and nucleotides contains a nucleotide content which isselected from the group consisting of about 1000 mg/day, of about 750mg/day, of about 500 mg/day, of about 250 mg/day, of about 100 mg/day,of about 75 mg/day, of about 50 mg/day, and of about 25 mg/day ofnucleotide.
 13. A method of preventing and/or treating a pathogenicinfection in a patient, the method comprising the steps of: selecting apatient in need of preventing and/or treating a pathogenic infection;—administering to the patient at least one agent which depletesguanosine-containing nucleosides and nucleotides; wherein the pathogenicinfection is selected from the group consisting of Borrelia burgdorferi,Babesia, and combinations thereof, wherein the pathogenic infection isprevented and/or treated in the patient.
 14. The method of claim 13,wherein the at least one agent which depletes guanosine-containingnucleosides and nucleotides is selected from the group consisting ofmycophenolate, IMPDH enzyme inhibitors, agents which bind to guanine, orguanosine-containing nucleosides and nucleotides, and combinationsthereof.
 15. A method of preventing and/or treating a pathogenicinfection in a patient, the method comprising the steps of: selecting apatient in need of preventing and/or treating a pathogenic infection;administering to the patient a diet which depletes guanosine-containingnucleosides and nucleotides; wherein the pathogenic infection isselected from the group consisting of Borrelia burgdorferi, Babesia, andcombinations thereof, wherein the pathogenic infection is preventedand/or treated in the patient.
 16. The method of claim 15, wherein thediet which depletes guanosine-containing nucleosides and nucleotidescontains a nucleotide content which is selected from the groupconsisting of about 1000 mg/day, of about 750 mg/day, of about 500mg/day, of about 250 mg/day, of about 100 mg/day, of about 75 mg/day, ofabout 50 mg/day, and of about 25 mg/day of nucleotide.
 17. A method ofpreventing and/or treating a pathogenic infection in a patient, themethod comprising the steps of: (i) selecting a patient in need ofpreventing and/or treating a pathogenic infection; (ii) administering tothe patient at least one agent which depletes guanosine-containingnucleosides and nucleotides; and (iii) prior to, concurrently with, orsubsequently to step (ii), administering to the patient a diet whichdepletes guanosine-containing nucleosides and nucleotides; wherein thepathogenic infection is selected from the group consisting of Borreliaburgdorferi, Babesia, and combinations thereof, wherein the pathogenicinfection is prevented and/or treated in the patient.
 18. The method ofclaim 17, wherein the at least one agent which depletesguanosine-containing nucleosides and nucleotides is selected from thegroup consisting of mycophenolate, IMPDH enzyme inhibitors, agents whichbind to guanine, or guanosine-containing nucleosides and nucleotides,and combinations thereof.
 19. The method of claim 17, wherein the dietwhich depletes guanosine-containing nucleosides and nucleotides containsa nucleotide content which is selected from the group consisting ofabout 1000 mg/day, of about 750 mg/day, of about 500 mg/day, of about250 mg/day, of about 100 mg/day, of about 75 mg/day, of about 50 mg/day,and of about 25 mg/day of nucleotide.
 20. A method of preventing a viralinfection in a patient, the method comprising the steps of: (i)selecting a patient in need of preventing a pathogenic infection; (ii)administering to the patient at least one agent which depletesguanosine-containing nucleosides and nucleotides; and (iii) prior to,concurrently with, or subsequently to step (ii), administering to thepatient a diet which depletes guanosine-containing nucleosides andnucleotides; wherein the viral infection is selected from the groupconsisting of flaviviridae virus, respiratory virus, and combinationsthereof, wherein the viral infection is prevented in the patient. 21.The method of claim 20, wherein the flaviviridae virus is selected fromthe group consisting of Absettarov virus, Alfuy virus Apoi virus Aroavirus, Bagaza virus Border disease virus Bouboui virus Bovine diarrheavirus Bussuquara virus Bukalasa bat virus, Dengue virus group, Hogcholera virus, Zika virus, Yellow fever virus; Dengue virus; St. Louisencephalitis virus; Japanese encephalitis virus; Tick-borne encephalitisvirus; Omsk hemorrhagic fever virus; Al Khumra virus; Kyasanur Forestdisease virus; Louping ill virus; West Nile virus; Kunjin virus; MurrayValley fever virus; Powassan virus; Hepatitis C virus; Hepatitis Gvirus, and combinations thereof.
 22. The method of claim 20, wherein therespiratory virus is selected from the group consisting of Influenzavirus type A, Influenza A H3N2; Influenza A H5N1 (low path); Influenza B(Victoria); Influenza B (Yamagata); Parainfluenza virus-3;Rhinovirus-14; Influenza A H7N9 virus; Influenza A H5N1 (high path),Adenoviruses, Avian influenza, Measles, Parainfluenza virus, Respiratorysyncytial virus (RSV), Rhinoviruses, SARS coronavirus, and combinationsthereof.
 23. The method of claim 20, wherein the at least one agentwhich depletes guanosine-containing nucleosides and nucleotides isselected from the group consisting of mycophenolate, IMPDH enzymeinhibitors, agents which bind to guanine, or guanosine-containingnucleosides and nucleotides, and combinations thereof.
 24. The method ofclaim 20, wherein the diet which depletes guanosine-containingnucleosides and nucleotides contains a nucleotide content which isselected from the group consisting of about 1000 mg/day, of about 750mg/day, of about 500 mg/day, of about 250 mg/day, of about 100 mg/day,of about 75 mg/day, of about 50 mg/day, and of about 25 mg/day ofnucleotide.